Protease homologs

Abstract

The invention relates to polynucleotides encoding newly identified protease homologs belonging to the superfamily of G-protein-coupled proteases. The invention also relates to the proteases. The invention further relates to methods using the protease polypeptides and polynucleotides as a target for diagnosis and treatment in protease-mediated disorders. The invention further relates to drug-screening methods using the protease polypeptides and polynucleotides to identify agonists and antagonists for diagnosis and treatment. The invention further encompasses agonists and antagonists based on the protease polypeptides and polynucleotides. The invention further relates to procedures for producing the protease polypeptides and polynucleotides.

Description

FIELD OF THE INVENTION

The invention relates to newly identified polynucleotides having homology to various protease families. The invention also relates to protease polypeptides. The invention further relates to methods using the protease polypeptides and polynucleotides as a target for diagnosis and treatment in protease-mediated disorders. The invention further relates to drug-screening methods using the protease polypeptides and polynucleotides to identify agonists and antagonists for diagnosis and treatment. The invention further encompasses agonists and antagonists based on the protease polypeptides and polynucleotides. The invention further relates to procedures for producing the protease polypeptides and polynucleotides.

BACKGROUND OF THE INVENTION

Proteases are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown protease nucleic acids and polypeptides. The present invention advances the state of the art by providing previously unidentified human protease sequences.

SUMMARY OF THE INVENTION

It is an object of the invention to identify novel proteases.

It is a further object of the invention to provide novel protease polypeptides that are useful as reagents or targets in protease assays applicable to treatment and diagnosis of protease-mediated disorders.

It is a further object of the invention to provide polynucleotides corresponding to the novel protease polypeptides that are useful as targets and reagents in protease assays applicable to treatment and diagnosis of protease-mediated disorders and useful for producing novel protease polypeptides by recombinant methods.

A specific object of the invention is to identify compounds that act as agonists and antagonists and modulate the expression of the novel proteases.

A further specific object of the invention is to provide compounds that modulate expression of the proteases for treatment and diagnosis of protease-related disorders.

The present invention is based on the discovery of novel nucleic acid molecules that are homologous to protease sequences.

Thus, in one aspect, the invention provides an isolated nucleic acid molecule that comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements of SEQ ID NOS: 1-268.

In another aspect, the invention provides isolated proteins and polypeptides encoded by nucleic acid molecules of the invention.

In another embodiment, the invention provides an isolated nucleic acid molecule that comprises a nucleotide sequence that is at least about 60% identical, preferably at least about 80% identical, preferably at least about 85% identical, more preferably at least about 90% identical, and even more preferably at least about 95% identical, and most preferably about 98% or more identical to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements of SEQ ID NOS: 1-268.

The invention also provides isolated variant polypeptides.

The invention also provides an isolated fragment or portion of any of SEQ ID NOS: 1-268 and the complement of SEQ ID NOS: 1-268. In preferred embodiments, the fragment is useful as a probe or primer, and/or is at least 15, more preferably at least 18, even more preferably 20-25, 30, 50, 100, 200 or more nucleotides in length.

The invention also provides isolated fragments of the polypeptides.

In another embodiment, the invention provides an isolated nucleic acid molecule that hybridizes under high stringency conditions to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements of SEQ ID NOS: 1-268.

The invention further provides nucleic acid constructs comprising the nucleic acid molecules described above. In a preferred embodiment, the nucleic acid molecules of the invention are operatively linked to a regulatory sequence.

The invention also provides vectors and host cells for expressing the protease nucleic acid molecules and polypeptides and particularly recombinant vectors and host cells.

The invention also provides methods of making the vectors and host cells and methods for using them to produce the protease nucleic acid molecules and polypeptides.

The invention also provides antibodies or antigen-binding fragments thereof that selectively bind the protease polypeptides and fragments.

The invention also provides methods of screening for compounds that modulate expression or activity of the protease polypeptides or nucleic acid (RNA or DNA).

The invention also provides a process for modulating protease polypeptide or nucleic acid expression or activity, especially using the screened compounds. Modulation may be used to treat conditions related to aberrant activity or expression of the protease polypeptides or nucleic acids.

The invention also provides assays for determining the presence or absence of and level of the protease polypeptides or nucleic acid molecules in a biological sample, including for disease diagnosis.

The invention also provides assays for determining the presence of a mutation in the protease polypeptides or nucleic acid molecules, including for disease diagnosis.

In still a further embodiment, the invention provides a computer readable means containing the nucleotide and/or amino acid sequences of the nucleic acids and polypeptides of the invention, respectively.

DETAILED DESCRIPTION OF THE INVENTION

Eucaryotic and Viral Aspartyl Active Sites

Aspartyl proteases, also known as acid proteases, (EC 3.4.23.-), are a widely distributed family of proteolytic enzymes (Foltman (1981) Essays Biochem 17:52-84; Davis (1990) Annu. Rev. Biophys. Chem. 19: 189-215; Rao et al. (1991) Biochemistry 30: 4663-4671) that exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains. Each domain contains an active site centered on a catalytic aspartyl residue. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain. Currently known eukaryotic aspartyl proteases include, but are not limited to:

Vertebrate gastric pepsins A and C (also known as gastricsin).

Vertebrate chymosin (rennin), involved in digestion and used for making cheese.

Vertebrate lysosomal cathepsins D (EC 3.4.23.5) and E (EC 3.4.23.34).

Mammalian renin (EC 3.4.23.15) whose function is to generate angiotensin I from angiotensinogen in the plasma.

Fungal proteases such as aspergillopepsin A (EC 3.4.23.18), candidapepsin (EC 3.4.23.24), mucoropepsin (EC 3.4.23.23) (mucor rennin), endothiapepsin (EC 3.4.23.22), polyporopepsin (EC 3.4.23.29), and rhizopuspepsin (EC 3.4.23.21).

Yeast saccharopepsin (EC 3.4.23.25) (proteinase A) (gene PEP4). PEP4 is implicated in posttranslational regulation of vacuolar hydrolases.

Yeast barrierpepsin (EC 3.4.23.35) (gene BAR1), a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone.

Fission yeast sxal which is involved in degrading or processing the mating pheromones.

Most retroviruses and some plant viruses, such as badnaviruses, encode an aspartyl protease which is an homodimer of a chain of about 95 to 125 amino acids. In most retroviruses, the protease is encoded as a segment of a polyprotein which is cleaved during the maturation process of the virus. It is generally part of the pol polyprotein and, more rarely, of the gag polyprotein.

Family Active Sites

Interleukin-1 beta converting enzyme (EC 3.4.22.36) (ICE) (Thornberry et al. (1995) Protein Sci. 4:3-12; Kumar (1995) Trends Biochem. Sci. 20:198-202) is responsible for the cleavage of the IL-1 beta precursor at an Asp-Ala bond to generate the mature biologically active cytokine. ICE a thiol protease composed of two subunits of 10 (p10) and 20 Kd (p20), both derived by the autocleavage of a 45 Kd precursor (p45). Two residues are implicated in the catalytic mechanism: a cysteine and an histidine. ICE belongs to a family of peptidases (Nicholson et al. (1997) Trends Biochem Sci. 22:299-306) which is implicated in programmed cell death (apoptosis) and which has been termed `caspase` for cysteine aspase. ICE is known as Caspase-1 and the other members of this family (Alnemri et al. (1996) Cell 87:171-171) include, but are not limited to:

Caspase-2 (ICH-1, NEDD-2).

Caspase-3 (also known as apopain, CPP32, Yama), a protease which, at the onset of apoptosis, proteolytically cleaves poly(ADP-ribose) polymerase (see) at an Asp-Gly bond.

Caspase-4 (ICH-2, TX, ICErel-II).

Caspase-5 (ICH-3, TY, ICErel-III).

Caspase-6 (MCH-2).

Caspase-7 (MCH-3, ICE-LAP3, CMH-1, SCA-2, LICE2).

Caspase-8 (MCH-5, MACH, FLICE).

Caspase-9 (MCH-6, ICE-LAP6).

Caspase-10 (MCH-4, FLICE2).

Caspase-11.

Caspase-12.

Caenorhabditis elegans ced-3 involved in the initiation of apoptosis.

Drosophila Ice.

Eukaryotic Thiol (Cysteine) Proteases Active Sites

Eukaryotic thiol proteases (EC 3.4.22.-) (Dufour (1988) Biochimie 70:1335-1342) are a family of proteolytic enzymes which contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad. Proteases that belong to this family include, but are limited to:

Vertebrate lysosomal cathepsins B (EC 3.4.22.1), H (EC 3.4.22.16), L (EC 3.4.22.15), and S (EC 3.4.22.27) (Kirschke et al. (1995) Protein Prof. 2:1587-1643).

Vertebrate lysosomal dipeptidyl peptidase I (EC 3.4.14.1) (also known as cathepsin C) (Kirschke et al. (1995) Protein Prof. 2:1587-1643).

Vertebrate calpains (EC 3.4.22.17). Calpains are intracellular calcium-activated thiol protease that contain both N-terminal catalytic domain and a C-terminal calcium-binding domain.

Mammalian cathepsin K, which seems involved in osteoclastic bone resorption (Shi et al. (1995) FEBS Lett. 357:129-134).

Human cathepsin O (Velasco et al. (1994) J. Biol. Chem. 269:27136-27142).

Bleomycin hydrolase. An enzyme that catalyzes the inactivation of the antitumor drug BLM (a glycopeptide).

Plant enzymes: barley aleurain (EC 3.4.22.16), EP-B1/B4; kidney bean EP-C1, rice bean SH-EP; kiwi fruit actinidin (EC 3.4.22.14); papaya latex papain (EC 3.4.22.2), chymopapain (EC 3.4.22.6), caricain (EC 3.4.22.30), and proteinase IV (EC 3.4.22.25); pea turgor-responsive protein 15A; pineapple stem bromelain (EC 3.4.22.32); rape COT44; ice oryzain Ipha, beta, and gamma; tomato low-temperature induced, Arabidopsis thaliana A494, RD19A and RD21 A.

House-dust mites allergens DerP1 and EurM1.

Cathepsin B-like proteinases from the worms Caenorhabditis elegans (genes gcp-1, cpr-3, cpr-4, cpr-5 and cpr-6), Schistosoma mansoni (antigen SM31) and Japonica (antigen SJ31), Haemonchus contortus (genes AC-1 and AC-2), and Ostertagia ostertagi (CP-1 and CP-3).

Slime mold cysteine proteinases CP1 and CP2.

Cruzipain from Trypanosoma cruzi and brucei.

Throphozoite cysteine proteinase (TCP) from various Plasmodium species.

Proteases from Leishmania mexicana, Theileria annulata and Theileria parva.

Baculoviruses cathepsin-like enzyme (v-cath).

Drosophila small optic lobes protein (gene sol), a neuronal protein that contains a calpain-like domain.

Yeast thiol protease BLH1/YCP1/LAP3.

Caenorhabditis elegans hypothetical protein C06G4.2, a calpain-like protein.

Two bacterial peptidases are also part of this family:

Aminopeptidase C from Lactococcus lactis (gene pepC) (Chapot-Chartier et al. (1993) Appl. Environ. Microbiol 59:330-333).

Thiol protease tpr from Porphyromonas gingivalis.

Three other proteins are structurally related to this family, but may have lost their proteolytic activity.

Soybean oil body protein P34. This protein has its active site cysteine replaced by a glycine.

Rat testin, a sertoli cell secretory protein highly similar to cathepsin L but with the active site cysteine is replaced by a serine. Rat testin should not be confused with mouse testin which is a LIM-domain protein (see).

Plasmodium falciparum serine-repeat protein (SERA), the ajor blood stage antigen. This protein of 111 Kd possesses a C-terminal thiol-protease-like domain Higgins et al. (1989) Nature 340:604-604), but the active site cysteine is replaced by a serine.

The sequences around the three active site residues are well conserved and can be used as signature patterns.

Cytosol Aminopeptidase Signature

Cytosol aminopeptidase is a eukaryotic cytosolic zinc-dependent exopeptidase that catalyzes the removal of unsubstituted amino-acid residues from the N-terminus of proteins. This enzyme is often known as leucine aminopeptidase (EC 3.4.11.1) (LAP) but has been shown (Matsushima et al. (1991) Biochem. Biophys. Res. Commun. 178:1459-1464) to be identical with prolyl aminopeptidase (EC 3.4.11.5). Cytosol aminopeptidase is a hexamer of identical chains, each of which binds two zinc ions.

Cytosol aminopeptidase is highly similar to Escherichia coli pepA, a manganese dependent aminopeptidase. Residues involved in zinc ion-binding (Burley et al. (1992) J. Mol. Biol. 224:113-140) in the mammalian enzyme are absolutely conserved in pepA where they presumably bind manganese.

A cytosol aminopeptidase from Rickettsia prowazekii (Wood et al. (1993) J. Bacteriol. 175:159-165) and one from Arabidopsis thaliana also belong to this family.

Neutral Zinc Metallopeptidases, Zinc-Binding Region Signature

The majority of zinc-dependent metallopeptidases (with the notable exception of the carboxypeptidases) share a common pattern of primary structure (Jongeneel et al. (1989) FEBS Lett. 242:211-214; Murphy et al.((991) FEBS Lett. 289:4-7) in the part of their sequence involved in the binding of zinc, and can be grouped together as a superfamily on the basis of this sequence similarity. They can be classified into a number of distinct families (Rawlings et al. (1995) Meth. Enzymol. 248:183-228) listed below along with some proteases that belong to these families:

Family M1

Bacterial aminopeptidase N (EC 3.4.11.2) (gene pepN).

Mammalian aminopeptidase N (EC 3.4.11.2).

Mammalian glutamyl aminopeptidase (EC 3.4.11.7) (aminopeptidase A). It may play a role in regulating growth and differentiation of early B-lineage cells.

Yeast aminopeptidase yscII (gene APE2).

Yeast alanine/arginine aminopeptidase (gene AAP1).

Yeast hypothetical protein YIL137c.

Leukotriene A-4 hydrolase (EC 3.3.2.6). This enzyme is responsible or the hydrolysis of an epoxide moiety of LTA-4 to form LTB-4; it has been shown (Medina et al.I (1991) Proc. Natl. Acad. Sci. U.S.A. 88:7620-7624) that it binds zinc and is capable of peptidase activity.

Family M2

Angiotensin-converting enzyme (EC 3.4.15.1) (dipeptidyl carboxypeptidase I) (ACE) the enzyme responsible for hydrolyzing angiotensin I to angiotensin II. There are two forms of ACE: a testis-specific isozyme and a somatic isozyme which has two active centers (Ehlers et al. (1991) Biochemistry 30:7118-7126).

Family M3

Thimet oligopeptidase (EC 3.4.24.15), a mammalian enzyme involved in the cytoplasmic degradation of small peptides.

Neurolysin (EC 3.4.24.16) (also known as mitochondrial oligopeptidase M or microsomal endopeptidase).

Mitochondrial intermediate peptidase precursor (EC 3.4.24.59) (MIP). It is involved the second stage of processing of some proteins imported in the mitochondrion.

Yeast saccharolysin (EC 3.4.24.37) (proteinase yscD) (Buchler et al. (1994) Eur. J. Biochem. 219:627-639).

Escherichia coli and related bacteria dipeptidyl carboxypeptidase (EC 3.4.15.5) (gene dcp).

Escherichia coli and related bacteria oligopeptidase A (EC 3.4.24.70) (gene opdA or prlC).

Yeast hypothetical protein YKL134c.

Family M4

Thermostable thermolysins (EC 3.4.24.27), and related thermolabile neutral proteases (bacillolysins) (EC 3.4.24.28) from various species of Bacillus.

Pseudolysin (EC 3.4.24.26) from Pseudomonas aeruginosa (gene lasB).

Extracellular elastase from Staphylococcus epidermidis.

Extracellular protease prt1 from Erwinia carotovora.

Extracellular minor protease smp from Serratia marcescens.

Vibriolysin (EC 3.4.24.25) from various species of Vibrio.

Protease prtA from Listeria monocytogenes.

Extracellular proteinase proA from Legionella pneumophila.

Family M5

Mycolysin (EC 3.4.24.31) from Streptomyces cacaoi.

Family M6

Immune inhibitor A from Bacillus thuringiensis (gene ina). Ina degrades two classes of insect antibacterial proteins, attacins and cecropins.

Family M7

Streptomyces extracellular small neutral proteases

Family M8

Leishmanolysin (EC 3.4.24.36) (surface glycoprotein gp63), a cell surface protease from various species of Leishmania.

Family M9

Microbial collagenase (EC 3.4.24.3) from Clostridium perfringens and Vibrio alginolyticus.

Family M10A

Serralysin (EC 3.4.24.40), an extracellular metalloprotease from Serratia.

Alkaline metalloproteinase from Pseudomonas aeruginosa (gene aprA).

Secreted proteases A, B, C and G from Erwinia chrysanthemi.

Yeast hypothetical protein YIL108w.

Family M10B

Mammalian extracellular matrix metalloproteinases (known as matrixins) (Woessner (1991) FASEB J. f:2145-2154): MMP-1 (EC 3.4.24.7) (interstitial collagenase), MMP-2 (EC 3.4.24.24) (72 Kd gelatinase), MMP-9 (EC 3.4.24.35) (92 Kd gelatinase), MMP-7 (EC 3.4.24.23) (matrylisin), MMP-8 (EC 3.4.24.34) (neutrophil collagenase), MMP-3 (EC 3.4.24.17) (stromelysin-1), MMP-10 (EC 3.4.24.22) (stromelysin-2), and MMP-11 (stromelysin-3), MMP-12 (EC 3.4.24.65) (macrophage metalloelastase).

Sea urchin hatching enzyme (envelysin) (EC 3.4.24.12), a protease that allows the embryo to digest the protective envelope derived from the egg extracellular matrix.

Soybean metalloendoproteinase 1.

Family M11

Chlamydomonas reinhardtii gamete lytic enzyme (GLE).

Family M12A

Astacin (EC 3.4.24.21), a crayfish endoprotease.

Meprin A (EC 3.4.24.18), a mammalian kidney and intestinal brush border metalloendopeptidase.

Bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and which expresses metalloendopeptidase activity. The Drosophila homolog of BMP-1 is the dorsal-ventral patterning protein tolloid.

Blastula protease 10 (BP10) from Paracentrotus lividus and the related protein SpAN from Strongylocentrotus purpuratus.

Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5.

Choriolysins L and H (EC 3.4.24.67) (also known as embryonic hatching proteins LCE and HCE) from the fish Oryzias lapides. These proteases participates in the breakdown of the egg envelope, which is derived from the egg extracellular matrix, at the time of hatching.

Family M12B

Snake venom metalloproteinases (Hite et al. (1992) Bio. Chem. Hoppe-Seyler 373:381-385). This subfamily mostly groups proteases that act in hemorrhage. Examples are: adamalysin II (EC 3.4.24.46), atrolysin C/D (EC 3.4.24.42), atrolysin E (EC 3.4.24.44), fibrolase (EC 3.4.24.72), trimerelysin I (EC 3.4.25.52) and II (EC 3.4.25.53).

Mouse cell surface antigen MS2.

Family M13

Mammalian neprilysin (EC 3.4.24.11) (neutral endopeptidase) (NEP).

Endothelin-converting enzyme 1 (EC 3.4.24.71) (ECE-1), which process the precursor of endothelin to release the active peptide.

Kell blood group glycoprotein, a major antigenic protein of erythrocytes.

The Kell protein is very probably a zinc endopeptidase.

Peptidase O from Lactococcus lactis (gene pepO).

Family M27

Clostridial neurotoxins, including tetanus toxin (TeTx) and the various botulinum toxins (BoNT). These toxins are zinc proteases that block neurotransmitter release by proteolytic cleavage of synaptic proteins such as synaptobrevins, syntaxin and SNAP-25 (Montecucco et al. (1993) Trends Biochem. Sci. 18:324-327; Niemann et a. (1994) Trends Cell Biol. 4:179-185).

Family M30

Staphylococcus hyicus neutral metalloprotease.

Family M32

Thermostable carboxypeptidase 1 (EC 3.4.17.19) (carboxypeptidase Taq), an enzyme from Thermus aquaticus which is most active at high tempertature.

Family M34

Lethal factor (LF) from Bacillus anthracis, one of the three proteins composing the anthrax toxin.

Family M35

Deuterolysin (EC 3.4.24.39) from Penicillium citrinum and related proteases from various species of Aspergillus.

Family M36

Extracellular elastinolytic metalloproteinases from Aspergillus.

From the tertiary structure of thermolysin, the position of the residues acting as zinc ligands and those involved in the catalytic activity are known. Two of the zinc ligands are histidines which are very close together in the sequence; C-terminal to the first histidine is a glutamic acid residue which acts as a nucleophile and promotes the attack of a water molecule on thecarbonyl carbon of the substrate.

Aminopeptidase P and Proline Dipeptidase Signature

Aminopeptidase P (EC 3.4.11.9) is the enzyme responsible for the release of any N-terminal amino acid adjacent to a proline residue. Proline dipeptidase (EC 3.4.13.9) (prolidase) splits dipeptides with a prolyl residue in the carboxyl terminal position.

Bacterial aminopeptidase P II (gene pepP) (Yoshimoto et al. (1989) J. Biochem. 105:412-416), proline dipeptidase (gene pepQ) (Nakahigashi et al. (1990) Nucleic Acids Res. 18:6439-6439), and human proline dipeptidase (gene PEPD) (Endo et al. (1989) J. Biol chem. 264: 4476-4481) are evolutionary related. These proteins are manganese metalloenzymes.

Yeast hypothetical proteins YER078c and YFR006w and Mycobacterium tuberculosis hypothetical protein MtCY49.29c also belong to this family.

Methionine Aminopeptidase Signatures

Methionine aminopeptidase (EC 3.4.11.18) (MAP) is responsible for the removal of the amino-terminal (initiator) methionine from nascent eukaryotic cytosolic and cytoplasmic prokaryotic proteins if the penultimate amino acid is small and uncharged. All MAP studied to date are monomeric proteins that require cobalt ions for activity.

Two subfamilies of MAP enzymes are known to exist (Arfin et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92:7714-1128; Keeling et al. (1996) Trends Biochem. Sci. 21:285-286). While being evolutionary related, they only share a limited amount of sequence similarity mostly clustered around the residues shown, in the Escherichia coli MAP (Roderick et al. (1993) Biochemistry 32:3907-3912), to be involved in cobalt-binding.

The first family consists of enzymes from prokaryotes as well as eukaryotic MAP-1, while the second group is made up of archebacterial MAP and eukaryotic MAP-2. The second subfamily also includes proteins which do not seem to be MAP, but that are clearly evolutionary related such as mouse proliferation-associated protein 1 and fission yeast curved DNA-binding protein.

Matrixins Cysteine Switch

Mammalian extracellular matrix metalloproteinases (EC 3.4.24.-), also known as matrixins (Woessner (1991) FASEB J. 5:2145-2154) (see ), are zinc-dependent enzymes. They are secreted by cells in an inactive form (zymogen) that differs from the mature enzyme by the presence of an N-terminal propeptide. A highly conserved octapeptide is found two residues downstream of the C-terminal end of the propeptide. This region has been shown to be involved in autoinhibition of matrixins (Sanchez-Lopez et al. (1988) J. Biol. Chem. 266:11892-11899; Parks et al. (1991) J. Biol. Chem. 266:1584-1590); a cysteine within the octapeptide chelates the active site zinc ion, thus inhibiting the enzyme. This region has been called the "cysteine switch" or "autoinhibitor region".

A cysteine switch has been found in the following zinc proteases:

MMP-1 (EC 3.4.24.7) (interstitial collagenase).

MMP-2 (EC 3.4.24.24) (72 Kd gelatinase).

MMP-3 (EC 3.4.24.17) (stromelysin-1).

MMP-7 (EC 3.4.24.23) (matrilysin).

MMP-8 (EC 3.4.24.34) (neutrophil collagenase).

MMP-9 (EC 3.4.24.35) (92 Kd gelatinase).

MMP-10 (EC 3.4.24.22) (stromelysin-2).

MMP-11 (EC 3.4.24.-) (stromelysin-3).

MMP-12 (EC 3.4.24.65) (macrophage metalloelastase).

MMP-13 (EC 3.4.24.-) (collagenase 3).

MMP-14 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 1).

MMP-15 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 2).

MMP-16 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 3).

Sea urchin hatching enzyme (EC 3.4.24.12) (envelysin) (Lepage et al. (1990) EMBO J. 93003-3012).

Chlamydomonas reinhardtii gamete lytic enzyme (GLE) (Kinshita et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89:4693-4697).

Serine Carboxypepidases, Active Sites

All known carboxypeptidases are either metallo carboxypeptidases or serine carboxypeptidases (EC 3.4.16.5 and EC 3.4.16.6). The catalytic activity of the serine carboxypeptidases, like that of the trypsin family serine proteases, is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which is itself hydrogen-bonded to aserine (Liao et al. (1990) J. Biol. Chem. 265:6528-6531). Proteins known to be serine carboxypeptidases include, but are not limited to:

Barley and wheat serine carboxypeptidases I, II, and III (Sorenson et al. (1989) Carlsberg Res. Commun. 54:193-202).

Yeast carboxypeptidase Y (YSCY) (gene PRC1), a vacuolar protease involved in degrading small peptides.

Yeast KEX1 protease, involved in killer toxin and alpha-factor precursor processing.

Fission yeast sxa2, a probable carboxypeptidase involved in degrading or processing mating pheromones (Imai et al. (1992) Mol. Cell. Biol. 12:1827-1834).

Penicillium janthinellum carboxypeptidase S1 (Svendsen et al. (1993) FEBS Lett. 333:39043).

Aspergullus niger carboxypeptidase pepF.

Aspergullus satoi carboxypeptidase cpdS.

Vertebrate protective protein/cathepsin A (Galjart et al. (1991) J. Biol. Chem 266:14754-14762), a lysosomal protein which is not only a carboxypeptidase but also essential for the activity of both beta-galactosidase and neuraminidase.

Mosquito vitellogenic carboxypeptidase (VCP) (Cho et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88:10821-10824).

Naegleria fowleri virulence-related protein Nf314 (Hu et al. (1992) Infect. Immun. 60:2418-2424).

Yeast hypothetical protein YBR139w.

Caenorhabditis elegans hypothetical proteins C08H9.1, F13D12.6, F32A5.3, F41C3.5 and K10B2.2.

This family also includes:

Sorghum (s)-hydroxymandelonitrile lyase (EC 4.1.2.11) (hydroxynitrile lyase) (HNL) (Wajant et al. (1994) Plant Mol. Biol. 26:735-746), an enzyme involved in plant cyanogenesis.

The sequences surrounding the active site serine and histidine residues are highly conserved in all these serine carboxypeptidases.

Proteasome A-type Subunits Signature

The proteasome (or macropain) (EC 3.4.99.46) (Rivett (1993) Biochem. J. 29:1-10; Rivett (1989) Arch. Biochem Biophys. 268:1-8; Goldbert et al. (1992) Nature 357:375-379; Wilk (1993) Enzyme Protein 47:187-188; Hilt et al. (1996) Trends Biochem. Sci. 21:96-102) is an eukaryotic and archaebacterial multicatalytic proteinase complex that seems to be involved in an ATP/ubiquitin-dependent nonlysosomal proteolytic pathway. In eukaryotes the proteasome is composed of about 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700 Kd.

Most proteasome subunits can be classified, on the basis on sequence similarities into two groups, A and B. Subunits that belong to the A-type group are proteins of from 210 to 290 amino acids that share a number of conserved sequence regions. Subunits that are known to belong to this family include, but are not limited to:

Vertebrate subunits C2 (nu), C3, C8, C9, iota and zeta.

Drosophila PROS-25, PROS-28.1, PROS-29 and PROS-35.

Yeast C1 (PRS1), C5 (PRS3), C7-alpha (Y8) (PRS2), Y7, Y13, PRE5, PRE6 and PUP2.

Arabidopsis thaliana subunits alpha and PSM30.

Thermoplasma acidophilum alpha-subunit. In this archaebacteria the proteasome is composed of only two different subunits.

Proteasome B-type Subunits Signature

The proteasome (or macropain) (EC 3.4.99.46) (Rivett (1993) Biochem. J. 29:1-10; Rivett (1989) Arch. Biochem Biophys. 268:1-8; Goldbert et al. (1992) Nature 357:375-379; Wilk (1993) Enzyme Protein 47:187-188; Hilt et al. (1996) Trends Biochem. Sci. 21:96-102) is an eukaryotic and archaebacterial multicatalytic proteinase complex that seems to be involved in an ATP/ubiquitin-dependent nonlysosomal proteolytic pathway. In eukaryotes the proteasome is composed of about 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700 Kd.

Most proteasome subunits can be classified, on the basis on sequence similarities into two groups, A and B. Subunits that belong to the B-type group are proteins of from 190 to 290 amino acids that share a number of conserved sequence regions. Subunits that belong to this family include, but are not limited to:

Vertebrate subunits C5, beta, delta, epsilon, theta (C10II), LMP2/RING12, C13 (LMP7/RING10), C7-I and MECL-1.

Yeast PRE1, PRE2 (PRG1), PRE3, PRE4, PRS3, PUPI and PUP3.

Drosophila L(3)73AI.

Fission yeast pts1.

Thermoplasma acidophilum beta-subunit. In this archaebacteria the proteasome is composed of only two different subunits.

Serine Proteases, Trypsin Family, Active Sites

The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases (Brenner (1988) Nature 334:528-530). Proteases that belong to the trypsin family include, but are not limited to:

Acrosin.

Blood coagulation factors VII, IX, X, XI and XII, thrombin, plasminogen, and protein C.

Cathepsin G.

Chymotrypsins.

Complement components C1r, C1s, C2, and complement factors B, D and I.

Complement-activating component of RA-reactive factor.

Cytotoxic cell proteases (granzymes A to H).

Duodenase I.

Elastases 1, 2, 3A, 3B (protease E), leukocyte (medullasin).

Enterokinase (EC 3.4.21.9) (enteropeptidase).

Hepatocyte growth factor activator.

Hepsin.

Glandular (tissue) kallikreins (including EGF-binding protein types A, B, and C, NGF-gamma chain, gamma-renin, prostate specific antigen (PSA) and tonin).

Plasma kallikrein.

Mast cell proteases (MCP) 1 (chymase) to 8.

Myeloblastin (proteinase 3) (Wegener's autoantigen).

Plasminogen activators (urokinase-type, and tissue-type).

Trypsins I, II, III, and IV.

Tryptases.

Snake venom proteases such as ancrod, batroxobin, cerastobin, flavoxobin,and protein C activator.

Collagenase from common cattle grub and collagenolytic protease from Atlantic sand fiddler crab.

Apolipoprotein(a).

Blood fluke cercarial protease.

Drosophila trypsin like proteases: alpha, easter, snake-locus.

Drosophila protease stubble (gene sb).

Major mite fecal allergen Der p III.

All the above proteins belong to family S1 in the classification of peptidases (Rawlings et al. (1994) Meth. Enzymol. 244:19-61) and originate from eukaryotic species. It should be noted that bacterial proteases that belong to family S2A are similar enough in the regions of the active site residues that they can be picked up by the same patterns. These proteases include, but are not limited to:

Achromobacter lyticus protease I.

Lysobacter alpha-lytic protease.

Streptogrisin A and B (Streptomyces proteases A and B).

Streptomyces griseus glutamyl endopeptidase II.

Streptomyces fradiae proteases 1 and 2.

Ubiquitin Carboxyl-Terminal Hydrolases Family 1 Cysteine Active Sites

Ubiquitin carboxyl-terminal hydrolases (EC 3.1.2.15) (UCH) (deubiquitinating enzymes) (Jentsch et al. (1991) Biochim. Biophys. Acta 1089:127-139) are thiol proteases that recognize and hydrolyze the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins.

There are two distinct families of UCH. The first class consist of enzymes of about 25 Kd and is currently represented by:

Mammalian isozymes L1 and L3.

Yeast YUH1.

Drosophila Uch.

One of the active site residues of class-I UCH (Johnston et al. (1997) EMBO J. 16:3787-3796) is a cysteine.

Ubiquitin Carboxyl-Terminal Hydrolases Family 2 Signatures

Ubiquitin carboxyl-terminal hydrolases (EC 3.1.2.15) (UCH) (deubiquitinating enzymes) (Jentsch et al. (1991) Biochim. Biophysi. Acta 1089:127-139) are thiol proteases that recognize and hydrolyze the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins.

There are two distinct families of UCH. The second class (Papa et al. (1993) Nature 366:313-319) consist of large proteins (800 to 2000 residues) and is represented by:

Yeast UBP1, UBP2, UBP3, UBP4 (or DOA4/SSV7), UBP5, UBP7, UBP9, UBP11, UBP12 and UBP13.

Yeast hypothetical protein YBR058c.

Yeast hypothetical protein YFR010w.

Yeast hypothetical protein YMR304w.

Yeast hypothetical protein YMR223w.

Yeast hypothetical protein YNL186w.

Human tre-2.

Human isopeptidase T.

Human isopeptidase T-3.

Mammalian Ode-1.

Mammalian Unp.

Mouse Dub-1.

Drosophila fat facets protein (gene faf).

Mammalian faf homolog.

Caenorhabditis elegans hypothetical protein R10E11.3.

Caenorhabditis elegans hypothetical protein K02C4.3.

These proteins only share two regions of similarity. The first region contains a conserved cysteine which is probably implicated in the catalytic mechanism. The second region contains two conserved histidines residues, one of which is also probably implicated in the catalytic mechanism.

The identification and characterization of the genes encoding the human proteases is described. The invention is based, at least in part, on the discovery of human genes encoding members of protease families, including but not limited to those described herein. The human protease family members were isolated based on a specific consensus motif or protein domain characteristic of a protease family of proteins. The search of the nucleic acid sequence database (usually derived from random cDNA library sequencing) was performed with one or more HMM motifs, a TBLASTN set, or both.

The TBLASTN set included a set of protein sequence probes which correspond to amino acid sequence motifs that are conserved in the protease family of proteins.

The HMM motif included a consensus sequence for a protein domain. Such consensus sequences can be found in a database of Hidden Markov Models (HMMs), e.g., the Pfam database, release 2.1, (http://www.sanger.ac.uk/Software/Pfam/HMM search). A description of the Pfam database can be found in Sonhammer et al. (1997) Proteins 23(3):405-420 and detailed description of HMMs can be found in, for example, Gribskov et al. (1990) Meth. Enzymol. 183:146-159; Gribskov et al. (1987) Proc. Natl. Acad. Sci. USA 84:4355-4358; Krogh et al. (1994) J. Mol. Biol. 235:1501-1531; and Stultz et al. (1993) Protein Sci. 2:305-314, the contents of which are incorporated herein by reference.

The sequences of the positive clones were determined and are set forth herein as SEQ ID NOS:1-268.

Polynucleotides

Accordingly, the invention provides isolated nucleic acid molecules comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. The Sequence Listing shows the relationship between each nucleotide sequence and protease family.

In one embodiment, the isolated nucleic acid molecule has the formula:

5'(R₁)_n -(R₂)-(R₃)_m 3'

wherein, at the 5' end of the molecule R₁ is either hydrogen or any nucleotide residue when n=1, and is any nucleotide residue when n>1; at the 3' end of the molecule R₃ is either hydrogen, a metal or any nucleotide residue when m=1, and is any nucleotide residue when m>1; n and m are integers between about 1 and 5000; and R₂ is a nucleic acid having a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements of SEQ ID NOS: 1-268. The R₂ nucleic acid is oriented so that its 5' residue is bound to the 3' molecule of R₁, and its 3' residue is bound to the 5' molecule of R₃. Any stretch of nucleic acid residues denoted by either R₁ or R₃, which is greater than 1, is preferably a heteropolymer, but can also be a homopolymer. In certain embodimentss, n and m are integers between about 1 and 2000, preferably between about 1 and 1000, and preferably between about 1 and 500. In other embodiments, the isolated nucleic acid molecule is at least about 50 nucleotides, preferably at least about 100 nucleotides, more preferably at least about 150 nucleotides, and even more preferably at least about 200 or more nucleotides in length. In still another embodiment, R₁ and R₃ are both hydrogen.

The term "protease polynucleotide" or "protease nucleic acid" refers to nucleic acid having the sequences shown in SEQ ID NO: 1-268 as well as variants and fragments of the polynucleotides of SEQ ID NO: 1-268.

An "isolated" protease nucleic acid is one that is separated from other nucleic acid present in the natural source of the protease nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. However, there can be some flanking nucleotide sequences, for example up to about 5 KB. The important point is that the nucleic acid is isolated from flanking sequences such that it can be subjected to the specific manipulations described herein such as recombinant expression, preparation of probes and primers, and other uses specific to the protease nucleic acid sequences.

Moreover, an "isolated" nucleic acid molecule, such as a cDNA or RNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. However, the nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated.

For example, recombinant DNA molecules contained in a vector or other construct (i.e., as part of a larger constructed nucleic acid) are considered isolated. Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

In some instances, the isolated material will form part of a composition (for example, a crude extract containing other substances), buffer system or reagent mix. In other circumstances, the material may be purified to essential homogeneity, for example as determined by PAGE or column chromatography such as HPLC. Preferably, an isolated nucleic acid comprises at least about 50, 80 or 90% (on a molar basis) of all macromolecular species present.

The invention provides isolated polynucleotides encoding protease polypeptides.

The nucleic acid molecule can include all or a portion of the coding sequence. In one embodiment, the protease nucleic acid comprises only the coding region. The polynucleotides include, but are not limited to, the sequence encoding the mature polypeptide alone or the sequence encoding the mature polypeptide and additional coding sequences, such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life or facilitate manipulation of a protein for assay or production, among other things. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes. The nucleic acid molecule can include the sequence encoding the mature polypeptide, with or without the additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5' and 3' sequences such as transcribed but non-translated sequences that play a role in transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding and stability of mRNA. In addition, the polynucleotide may be fused to a marker sequence encoding, for example, a peptide that facilitates purification, such as those described herein.

Protease polynucleotides can be in the form of RNA, such as mRNA, or in the form of DNA, including cDNA and genomic DNA, obtained by cloning or produced by chemical synthetic techniques or by a combination thereof The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the non-coding strand (anti-sense strand).

Protease nucleic acids comprise the nucleotide sequences shown in SEQ ID NOS: 1-268, corresponding to human protease cDNAs.

The invention further provides variant protease polynucleotides, and fragments thereof, that differ from the nucleotide sequence shown in SEQ ID NOS: 1-268 due to degeneracy of the genetic code and thus encode the same protein as that encoded by the nucleotide sequences shown in SEQ ID NOS: 1-268.

The invention also provides protease nucleic acid molecules encoding the variant polypeptides described herein. Such polynucleotides may be naturally occurring, such as allelic variants (same locus), homologs (different locus), and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Such non-naturally occurring variants may be made by mutagenesis techniques, including those applied to polynucleotides, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions.

Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions.

Typically, variants have a substantial identity with a nucleic acid molecule selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof.

Orthologs, homologs, and allelic variants can be identified using methods well known in the art. These variants comprise a nucleotide sequence encoding a protease that is 50-55% at least about 55%, typically at least about 70-75%, more typically at least about 80-85%, and most typically at least about 90-95% or more homologous to the nucleotide sequence shown herein or a fragment of these sequences. Such nucleic acid molecules can be readily identified as being able to hybridize under stringent conditions to a nucleotide sequence or fragments thereof selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. In one embodiment, the variants hybridize under high stringency hybridization conditions (e.g., for selective hybridization) to a nucleotide sequence selected from SEQ ID NOS: 1-268. It is understood that stringent hybridization does not indicate substantial homology where it is due to general homology, such as poly A sequences, or sequences common to all or most proteins, sequences common to all or most proteases, or sequences common to all or most members of the protease family to which the specific protease belongs. Moreover, it is understood that variants do not include any of the nucleic acid sequences that may have been disclosed prior to the invention.

As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences encoding a protease at least 50-55%, 55% homologous to each other typically remain hybridized to each other. The conditions can be such that sequences at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95% or more identical to each other remain hybridized to one another. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, incorporated by reference. One example of stringent hybridization conditions are hybridization in 6×sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65°C In another non-limiting example, nucleic acid molecules are allowed to hybridize in 6×sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more low stringency washes in 0.2×SSC/0.1% SDS at room temperature, or by one or more moderate stringency washes in 0.2×SSC/0. 1% SDS at 42°C, or washed in 0.2×SSC/0.1% SDS at 65°C for high stringency. In one embodiment, an isolated protease nucleic acid molecule that hybridizes under stringent conditions to the sequence of SEQ ID NOS: 1-268 corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

As understood by those of ordinary skill, the exact conditions can be determined empirically and depend on ionic strength, temperature and the concentration of destabilizing agents such as formamide or denaturing agents such as SDS. Other factors considered in determining the desired hybridization conditions include the length of the nucleic acid sequences, base composition, percent mismatch between the hybridizing sequences and the frequency of occurrence of subsets of the sequences within other non-identical sequences. Thus, equivalent conditions can be determined by varying one or more of these parameters while maintaining a similar degree of identity or similarity between the two nucleic acid molecules.

The present invention also provides isolated nucleic acids that contain a single or double stranded fragment or portion that hybridizes under stringent conditions to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements of SEQ ID NOS: 1-268. In one embodiment, the nucleic acid consists of a portion of a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements SEQ ID NOS: 1-268. The nucleic acid fragments of the invention are at least about 15, preferably at least about 18, 20, 23 or 25 nucleotides, and can be 30, 40, 50, 100, 200 or more nucleotides in length. Longer fragments, for example, 30 or more nucleotides in length, which encode antigenic proteins or polypeptides described herein are useful. Additionally, nucleotide sequences described herein can also be contigged to produce longer sequences (see, for example, http://bozeman.mbt.washington.edu/phrap.docs/phrap. html).

In a related aspect, the nucleic acid fragments of the invention provide probes or primers in assays such as those described below. "Probes" are oligonucleotides that hybridize in a base-specific manner to a complementary strand of nucleic acid. Such probes include polypeptide nucleic acids, as described in Nielsen et al., Science 254, 1497-1500 (1991). Typically, a probe comprises a region of nucleotide sequence that hybridizes under highly stringent conditions to at least about 15, typically about 20-25, and more typically about 40, 50 or 75 consecutive nucleotides of a nucleic acid selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. More typically, the probe further comprises a label, e.g., radioisotope, fluorescent compound, enzyme, or enzyme co-factor.

As used herein, the term "primer" refers to a single-stranded oligonucleotide which acts as a point of initiation of template-directed DNA synthesis using well-known methods (e.g., PCR, LCR) including, but not limited to those described herein. The appropriate length of the primer depends on the particular use, but typically ranges from about 15 to 30 nucleotides. The term "primer site" refers to the area of the target DNA to which a primer hybridizes. The term "primer pair" refers to a set of primers including a 5' (upstream) primer that hybridizes with the 5' end of the nucleic acid sequence to be amplified and a 3' (downstream) primer that hybridizes with the complement of the sequence to be amplified.

Fragments include nucleic acid sequences corresponding to specific amino acid sequences described herein. Further fragments can include subfragments of specific domains or sites, such as proteolytic cleavage sites, sites of interaction with a protein that modifies or activates the protease (an "effector" protein), or substrate binding sites. Nucleic acid fragments, according to the present invention, are not to be construed as encompassing those fragments that may have been disclosed prior to the invention.

Protease nucleic acid fragments include sequences corresponding to any domain described herein, subregions also described, and specific functional sites, such as binding and cleavage sites. Protease nucleic acid fragments also include combinations of the domains, regions, segments, and other functional sites described herein. A person of ordinary skill in the art would be aware of the many permutations that are possible.

It is understood that a protease fragment includes any nucleic acid sequence that does not include the entire gene.

Where the location of the domains or sites have been predicted by computer analysis, one of ordinary skill would appreciate that the amino acid residues constituting these domains can vary depending on the criteria used to define the domains.

The invention also provides protease nucleic acid fragments that encode epitope bearing regions of the protease proteins encoded by the cDNAs of the invention.

For example, the coding region of a protease gene can be isolated using the known nucleotide sequence to synthesize an oligonucleotide probe. A labeled probe can then be used to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in PCR reactions to clone specific regions of protease genes.

The nucleic acid molecules of the invention such as those described above can be identified and isolated using standard molecular biology techniques and the sequence information provided in SEQ ID NOS: 1-268. For example, nucleic acid molecules can be amplified and isolated by the polymerase chain reaction using synthetic oligonucleotide primers designed based on one or more of the sequences provided in SEQ ID NOS: 1-268 and the complements thereof. See generally PCR Technology: Principles and Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methods and Applications 1, 17 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202. The nucleic acid molecules can be amplified using cDNA, mRNA or genomic DNA as a template, cloned into an appropriate vector and characterized by DNA sequence analysis.

Other suitable amplification methods include the ligase chain reaction (LCR) (see Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989)), and self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)) and nucleic acid based sequence amplification (NASBA). The latter two amplification methods involve isothermal reactions based on isothermal transcription, which produce both single stranded RNA (ssRNA) and double stranded DNA (dsDNA) as the amplification products in a ratio of about 30 or 100 to 1, respectively.

Polynucleotide Uses

The nucleic acid sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

The protease polynucleotides are useful for probes, primers, and in biological assays. Where the polynucleotides are used to assess protease properties or functions, such as in the assays described herein, all or less than all of the entire cDNA can be useful. In this case, even fragments that may have been known prior to the invention are encompassed. Thus, for example, assays specifically directed to protease functions, such as assessing agonist or antagonist activity, encompass the use of known fragments. Further, diagnostic methods for assessing protease function can also be practiced with any fragment, including those fragments that may have been known prior to the invention. Similarly, in methods involving treatment of protease dysfunction, all fragments are encompassed including those which may have been known in the art.

The protease polynucleotides are useful as a hybridization probe for cDNA and genomic DNA to isolate a full-length cDNA and genomic clones encoding the protease polypeptides and to isolate cDNA and genomic clones that correspond to variants producing the same protease polypeptides or the other types of variants described herein. Variants can be isolated from the same tissue and organism from which the polypeptides were isolated, different tissues from the same organism, or from different organisms. This method is useful for isolating genes and cDNA that are developmentally-controlled and therefore may be expressed in the same tissue or different tissues at different points in the development of an organism.

The probe can correspond to any sequence along the entire length of the gene encoding the protease. Accordingly, it could be derived from 5' noncoding regions, the coding region, and 3' noncoding regions.

The nucleic acid probe can be, for example, the full-length cDNA sequence of SEQ ID NOS: 1-268, or fragments thereof, such as an oligonucleotide of at least 12, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to mRNA or DNA. For example, the nucleic acid probe can be all or a portion of SEQ ID NOS: 1-268, or the complement of SEQ ID NOS: 1-268, or a portion thereof. Other suitable probes for use in the diagnostic assays of the invention are described herein.

Fragments of the polynucleotides described herein are also useful to synthesize larger fragments or full-length polynucleotides described herein. For example, a fragment can be hybridized to any portion of an mRNA and a larger or full-length cDNA can be produced.

Antisense nucleic acids of the invention can be designed using the nucleotide sequences of SEQ ID NOS: 1-268, and constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Examples of modified nucleotides which can be used to generate the antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid) will be of an antisense orientation to a target nucleic acid of interest.

Additionally, the nucleic acid molecules of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorganic & Medicinal Chemistry 4:5). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. USA 93:14670. PNAs can be further modified, e.g., to enhance their stability, specificity or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996), supra, Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63, Mag et al. (1989) Nucleic Acids Res. 17:5973, and Peterser et al. (1975) Bioorganic Med. Chem. Lett. 5:1119.

The nucleic acid molecules and fragments of the invention can also include other appended groups such as peptides (e.g., for targeting host cell proteases in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al. (1989) Proc. Natl. Acad. Sci USA 86:6553-6556; Lemaitre et al. (1987) Proc. Natl. Acad. Sci. USA 84:648-652; PCT Publication No. WO88/0918) or the blood brain barrier (see, e.g., PCT Publication No. Wo89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al. (1988) Bio-Techniques 6:958-976) or intercalating agents (see, e.g., Zon (1988) Pharm Res. 5:539-549).

The protease polynucleotides are also useful as primers for PCR to amplify any given region of a protease polynucleotide.

The protease polynucleotides are also useful for constructing recombinant vectors. Such vectors include expression vectors that express a portion of, or all of, the protease polypeptides. Vectors also include insertion vectors, used to integrate into another polynucleotide sequence, such as into the cellular genome, to alter in situ expression of protease genes and gene products. For example, an endogenous protease coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced mutations.

The protease polynucleotides are also useful for expressing antigenic portions of the proteases.

The protease polynucleotides are also useful as probes for determining the chromosomal positions of the proteases by means of in situ hybridization methods.

Once the nucleic acid (or a portion of the sequence) has been isolated, it can be used to map the location of the gene on a chromosome. The mapping of the sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease. Briefly, genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the nucleic acid molecules described herein. Computer analysis of the sequences can be used to predict primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the appropriate nucleotide sequences will yield an amplified fragment.

PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycle. Using the nucleic acid molecules of the invention to design oligonucleotide primers, sublocalization can be achieved with panels of fragments from specific chromosomes. Other mapping strategies which can similarly be used to map a specified sequence to its chromosome include in situ hybridization (described in Fan, Y et al. (1990) PNAS, 97:6223-27), pre-screening with labeled flow-sorted chromosomes, and pre-selection by hybridization to chromosome specific cDNA libraries.

Fluorescence in situ hybridization (FISH) of a nucleotide sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical such as colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a nucleotide sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases will suffice to get good results at a reasonable amount of time. for a review of this technique, see Verma et al., Human Chromosomes: A Manual of Basic Techniques (Pergamon Press, New York 1988).

Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. (Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man, available on-line through Johns Hopkins University Welch Medical Library). The relationship between a gene and a disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, for example, Egeland, J. et al. (1987) Nature, 325:783-787.

Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with a specified gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible form chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

The polynucleotide probes are also useful to determine patterns of the presence of the gene encoding the proteases and their variants with respect to tissue distribution, for example, whether gene duplication has occurred and whether the duplication occurs in all or only a subset of tissues. The genes can be naturally-occurring or can have been introduced into a cell, tissue, or organism exogenously.

The polynucleotides are also useful for designing ribozymes corresponding to all, or a part, of the mRNA produced from genes encoding the polynucleotides described herein.

The polynucleotides are also useful for constructing host cells expressing a part, or all, of the protease polynucleotides and polypeptides.

The polynucleotides are also useful for constructing transgenic animals expressing all, or a part, of the protease polynucleotides and polypeptides.

The polynucleotides are also useful as hybridization probes for determining the level of protease nucleic acid expression. Accordingly, the probes can be used to detect the presence of, or to determine levels of, protease nucleic acid in cells, tissues, and in organisms. The nucleic acid whose level is determined can be DNA or RNA, including mRNA. Accordingly, probes corresponding to the polypeptides described herein can be used to assess gene copy number in a given cell, tissue, or organism. This is particularly relevant in cases in which there has been an amplification of the protease genes.

Alternatively, the probe can be used in an in situ hybridization context to assess the position of extra copies of the protease genes, as on extrachromosomal elements or as integrated into chromosomes in which the protease gene is not normally found, for example as a homogeneously staining region.

These uses are relevant for diagnosis of disorders involving an increase or decrease in protease expression relative to normal, such as a proliferative disorder, a differentiative or developmental disorder, or a hematopoietic disorder.

Thus, the present invention provides a method for identifying a disease or disorder associated with aberrant expression or activity of protease nucleic acid, in which a test sample is obtained from a subject and nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of the nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant expression or activity of the nucleic acid.

In vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detecting DNA includes Southern hybridizations and in situ hybridization.

Probes can be used as a part of a diagnostic test kit for identifying cells or tissues that express a protease, such as by measuring a level of a protease-encoding nucleic acid in a sample of cells from a subject e.g., mRNA or genomic DNA, or determining if a protease gene has been mutated.

Nucleic acid expression assays are useful for drug screening to identify compounds that modulate protease nucleic acid expression (e.g., antisense, polypeptides, peptidomimetics, small molecules or other drugs). A cell is contacted with a candidate compound and the expression of mRNA determined. The level of expression of protease mRNA in the presence of the candidate compound is compared to the level of expression of protease mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of nucleic acid expression based on this comparison and be used, for example to treat a disorder characterized by aberrant nucleic acid expression. The modulator may bind to the nucleic acid or indirectly modulate expression, such as by interacting with other cellular components that affect nucleic acid expression.

The invention thus provides a method for identifying a compound that can be used to treat a disorder associated with nucleic acid expression of the protease gene. The method typically includes assaying the ability of the compound to modulate the expression of the protease nucleic acid and thus identifying a compound that can be used to treat a disorder characterized by undesired protease nucleic acid expression.

The assays can be performed in cell-based and cell-free systems. Cell-based assays include cells naturally expressing the protease nucleic acid or recombinant cells genetically engineered to express specific nucleic acid sequences.

Modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject) in patients or in transgenic animals.

The assay for protease nucleic acid expression can involve direct assay of nucleic acid levels, such as mRNA levels, or on collateral compounds involved in the pathway in which the protease is found. Further, the expression of genes that are up- or down-regulated in response to the protease function in the pathway can also be assayed. In this embodiment the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

Accordingly, the invention provides methods of treatment, with the nucleic acid as a target, using a compound identified through drug screening as a gene modulator to modulate protease nucleic acid expression. Modulation includes both up-regulation (i.e. activation or agonization) or down-regulation (suppression or antagonization) or effects on nucleic acid activity (e.g. when nucleic acid is mutated or improperly modified) Treatment is of disorders characterized by aberrant expression or activity of nucleic acid.

One aspect of the invention relates to diagnostic assays for determining nucleic acid expression as well as activity in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual has a disease or disorder, or is at risk of developing a disease or disorder, associated with aberrant expression or activity. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with expression or activity of the nucleic acid molecules.

The protease polynucleotides are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of the protease gene in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as a barometer for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound could be commensurately decreased.

The monitoring can be, for example, as follows: (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a specified mRNA or genomic DNA of the invention in the pre-administration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the mRNA or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the mRNA or genomic DNA in the pre-administration sample with the mRNA or genomic DNA in the post-administration sample or samples; and (vi) increasing or decreasing the administration of the agent to the subject accordingly.

The protease polynucleotides are also useful in diagnostic assays for qualitative changes in protease nucleic acid, and particularly in qualitative changes that lead to pathology. The polynucleotides can be used to detect mutations in protease genes and gene expression products such as mRNA. The polynucleotides can be used as hybridization probes to detect naturally-occurring genetic mutations in a protease gene and thereby to determine whether a subject with the mutation is at risk for a disorder caused by the mutation. Mutations include deletion, addition, or substitution of one or more nucleotides in the gene, chromosomal rearrangement, such as inversion or transposition, modification of genomic DNA, such as aberrant methylation patterns or changes in gene copy number, such as amplification. Detection of a mutated form of a protease gene associated with a dysfunction provides a diagnostic tool for an active disease or susceptibility to disease when the disease results from overexpression, underexpression, or altered expression of a protease.

Individuals carrying mutations in the protease gene can be detected at the nucleic acid level by a variety of techniques. Genomic DNA can be analyzed directly or can be amplified by using PCR prior to analysis. RNA or cDNA can be used in the same way.

In certain embodiments, detection of the mutation involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g. U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al., Science 241:1077-1080 (1988); and Nakazawa et al., PNAS 91:360-364 (1994)), the latter of which can be particularly useful for detecting point mutations in the gene (see Abravaya et al., Nucleic Acids Res. 23:675-682 (1995)). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a gene under conditions such that hybridization and amplification of the gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. Deletions and insertions can be detected by a change in size of the amplified product compared to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to normal RNA or antisense DNA sequences. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (Guatelli, J. C. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., (1989) Proc. Natl. Acad. Sci. USA, 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al.,(1988) Bio/Technology, 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

Alternatively, mutations in a protease gene can be directly identified, for example, by alterations in restriction enzyme digestion patterns determined by gel electrophoresis.

Further, sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature.

Sequence changes at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or the chemical cleavage method.

Furthermore, sequence differences between a mutant protease gene and a wild-type gene can be determined by direct DNA sequencing. A variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv. Chromatogr. 36:127-162 (1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159 (1993)).

Other methods for detecting mutations in the gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985)); Cotton et al., PNAS 85:4397 (1988); Saleeba et al., Meth. Enzymol. 217:286-295 (1992)).

In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis, 15:1657-1662). According to an exemplary embodiment, a probe based on an nucleotide sequence of the invention is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, for example, U.S. Pat. No. 5,459,039. In other embodiments, electrophoretic mobility of mutant and wild type nucleic acid is compared (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat. Res. 285:125-144 (1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (Myers et al., Nature 313:495 (1985)). The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet., 7:5). Examples of other techniques for detecting point mutations include, selective oligonucleotide hybridization, selective amplification, and selective primer extension.

In other embodiments, genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotide probes (Cronin, M. T. et al. (1996) Human Mutation, 7:244-255; Kozal, M. J. et al.(1996) Nature Medicine, 2:753-759). For example, genetic mutations can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, M. T. et al. supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. "Pharmacogenomics", as used herein, refers to the application of genomics technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market.

Pharmacogenomics deal with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, e.g., Eichelbaum, M., Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 (1996), and Linder, M. W., Clin. Chem. 43(2):254-266 (1997). The clinical outcomes of these variations result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the genotype of the individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. Further, the activity of drug metabolizing enzymes effects both the intensity and duration of drug action. Thus, the pharmacogenomics of the individual permit the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic treatment based on the individual's genotype. The discovery of genetic polymorphisms in some drug metabolizing enzymes has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. Polymorphisms can be expressed in the phenotype of the extensive metabolizer and the phenotype of the poor metabolizer. Accordingly, genetic polymorphism may lead to allelic protein variants of the protease in which one or more of the protease functions in one population is different from those in another population.

The protease polynucleotides are thus useful for testing an individual for a genotype that while not necessarily causing the disease, nevertheless affects the treatment modality. Thus, the polynucleotides can be used to study the relationship between an individual's genotype and the individual's response to a compound used for treatment (pharmacogenomic relationship). In the present case, for example, a mutation in a protease gene that results in altered affinity for substrate or effector could result in an excessive or decreased drug effect with standard concentrations of effector that activates the protease or substrate cleaved by the protease. Accordingly, the protease polynucleotides described herein can be used to assess the mutation content of the protease gene in an individual in order to select an appropriate compound or dosage regimen for treatment.

Thus polynucleotides displaying genetic variations that affect treatment provide a diagnostic target that can be used to tailor treatment in an individual. Accordingly, the production of recombinant cells and animals containing these polymorphisms allow effective clinical design of treatment compounds and dosage regimens.

The methods can involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting mRNA, or genomic DNA, such that the presence of mRNA or genomic DNA is detected in the biological sample, and comparing the presence of mRNA or genomic DNA in the control sample with the presence of mRNA or genomic DNA in the test sample.

The protease polynucleotides are also useful for chromosome identification when the sequence is identified with an individual chromosome and to a particular location on the chromosome. First, the DNA sequence is matched to the chromosome by in situ or other chromosome-specific hybridization. Sequences can also be correlated to specific chromosomes by preparing PCR primers that can be used for PCR screening of somatic cell hybrids containing individual chromosomes from the desired species. Only hybrids containing the chromosome containing the gene homologous to the primer will yield an amplified fragment. Sublocalization can be achieved using chromosomal fragments. Other strategies include prescreening with labeled flow-sorted chromosomes and preselection by hybridization to chromosome-specific libraries. Further mapping strategies include fluorescence in situ hybridization which allows hybridization with probes shorter than those traditionally used. Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on the chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

The protease polynucleotides can also be used to identify individuals from small biological samples. This can be done for example using restriction fragment-length polymorphism (RFLP) to identify an individual. Thus, the polynucleotides described herein are useful as DNA markers for RFLP (See U.S. Pat. No. 5,272,057).

Furthermore, the protease sequence can be used to provide an alternative technique which determines the actual DNA sequence of selected fragments in the genome of an individual. Thus, the protease sequences described herein can be used to prepare two PCR primers from the 5' and 3' ends of the sequences. These primers can then be used to amplify DNA from an individual for subsequent sequencing.

Panels of corresponding DNA sequences from individuals prepared in this manner can provide unique individual identifications, as each individual will have a unique set of such DNA sequences. It is estimated that allelic variation in humans occurs with a frequency of about once per each 500 bases. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. The protease sequences can be used to obtain such identification sequences from individuals and from tissue. The sequences represent unique fragments of the human genome. Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. The noncoding sequences of these sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers which each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

If a panel of reagents from the sequences is used to generate a unique identification database for an individual, those same reagents can later be used to identify tissue from that individual. Using the unique identification database, positive identification of the individual, living or dead, can be made from extremely small tissue samples.

The protease polynucleotides can also be used in forensic identification procedures. PCR technology can be used to amplify DNA sequences taken from very small biological samples, such as a single hair follicle, body fluids (e.g. blood, saliva, or semen). The amplified sequence can then be compared to a standard allowing identification of the origin of the sample.

The protease polynucleofides can thus be used to provide polynucleotide reagents, e.g., PCR primers, targeted to specific loci in the human genome, which can enhance the reliability of DNA-based forensic identifications by, for example, providing another "identification marker" (i.e. another DNA sequence that is unique to a particular individual). As described above, actual base sequence information can be used for identification as an accurate alternative to patterns formed by restriction enzyme generated fragments. Sequences targeted to the noncoding region are particularly useful since greater polymorphism occurs in the noncoding regions, making it easier to differentiate individuals using this technique. Examples of polynucleotide reagents include the nucleic acid molecules or the invention, or portions thereof, e.g., fragments having a length of at least 20 bases, preferably at least 30 bases.

The protease polynucleotides can further be used to provide polynucleotide reagents, e.g., labeled or labelable probes which can be used in, for example, an in situ hybridization technique, to identify a specific tissue. This is useful in cases in which a forensic pathologist is presented with a tissue of unknown origin. Panels of protease probes can be used to identify tissue by species and/or by organ type.

In a similar fashion, these primers and probes can be used to screen tissue culture for contamination (i.e. screen for the presence of a mixture of different types of cells in a culture).

Alternatively, the protease polynucleotides can be used directly to block transcription or translation of protease gene sequences by means of antisense or ribozyme constructs. Thus, in a disorder characterized by abnormally high or undesirable protease gene expression, nucleic acids can be directly used for treatment.

The protease polynucleotides are thus useful as antisense constructs to control protease gene expression in cells, tissues, and organisms. A DNA antisense polynucleotide is designed to be complementary to a region of the gene involved in transcription, preventing transcription and hence production of protease protein. An antisense RNA or DNA polynucleotide would hybridize to the mRNA and thus block translation of mRNA into protease protein.

Examples of antisense molecules useful to inhibit nucleic acid expression include antisense molecules complementary to a fragment of any 5' untranslated regions present in SEQ ID NOS: 1-268 which also includes the start codon and antisense molecules which are complementary to a fragment of any 3' untranslated region present in SEQ ID NOS: 1-268.

Alternatively, a class of antisense molecules can be used to inactivate mRNA in order to decrease expression of protease nucleic acid. Accordingly, these molecules can treat a disorder characterized by abnormal or undesired protease nucleic acid expression. This technique involves cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible regions include coding regions and particularly coding regions corresponding to the catalytic and other functional activities of the protease protein, such as substrate binding and cleavage site.

The protease polynucleotides also provide vectors for gene therapy in patients containing cells that are aberrant in protease gene expression. Thus, recombinant cells, which include the patient's cells that have been engineered ex vivo and returned to the patient, are introduced into an individual where the cells produce the desired protease protein to treat the individual.

The invention also encompasses kits for detecting the presence of a protease nucleic acid in a biological sample. For example, the kit can comprise reagents such as a labeled or labelable nucleic acid (probe or primer) or agent capable of detecting protease nucleic acid in a biological sample; means for determining the amount of protease nucleic acid in the sample; and means for comparing the amount of protease nucleic acid in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect protease mRNA or DNA.

Polypeptides

The invention thus relates to novel proteases having the deduced amino acid sequences encoded by the open reading frames present in the nucleic acid molecules of SEQ ID NOS: 1-268.

The term "protease polypeptide" or "protease" refers to a protein sequence encoded by the nucleic acid sequences represented by SEQ ID NOS: 1-268. The term "protease" or "protease polypeptide", however, further includes the numerous variants described herein, as well as fragments derived from the polypeptides and variants.

The present invention thus provides an isolated or purified protease polypeptides and variants and fragments thereof.

As used herein, a polypeptide is said to be "isolated" or "purified" when it is substantially free of cellular material when it is isolated from recombinant and non-recombinant cells, or free of chemical precursors or other chemicals when it is chemically synthesized. A polypeptide, however, can be joined to another polypeptide with which it is not normally associated in a cell and still be considered "isolated" or "purified."

The polypeptides can be purified to homogeneity. It is understood, however, that preparations in which the polypeptide is not purified to homogeneity are useful and considered to contain an isolated form of the polypeptide. The critical feature is that the preparation allows for the desired function of the polypeptide, even in the presence of considerable amounts of other components. Thus, the invention encompasses various degrees of purity.

In one embodiment, the language "substantially free of cellular material" includes preparations of the polypeptide having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the polypeptide is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20%, less than about 10%, or less than about 5% of the volume of the protein preparation.

In some instances, the protease will be associated with cellular membranes. This could include intracellular membranes or the outer cellular membrane. In either case, a protease is considered isolated if it is part of a purified membrane preparation or if it is purified and then reconstituted into membrane vesicles or liposomes.

The language "substantially free of chemical precursors or other chemicals" includes preparations of the polypeptide in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of the polypeptide having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

In one embodiment, a polypeptide comprises an amino acid sequence encoded by a nucleic acid comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. However, the invention also encompasses sequence variants. Variants include a substantially homologous protein encoded by the same genetic locus in an organism, i.e., an allelic variant. Variants also encompass proteins derived from other genetic loci in an organism, but having substantial homology to a polypeptide encoded by a nucleic acid comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. Variants also include proteins substantially homologous to the protease but derived from another organism, i.e., an ortholog. Variants also include proteins that are substantially homologous to the protease that are produced by chemical synthesis. Variants also include proteins that are substantially homologous to the protease that are produced by recombinant methods. It is understood, however, that variants exclude any amino acid sequences disclosed prior to the invention.

As used herein, two proteins (or a region of the proteins) are substantially homologous when the amino acid sequences are at least about 50-55%, 55-60%, typically at least about 70-75%, more typically at least about 80-85%, and most typically at least about 90-95% or more homologous. A substantially homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid sequence hybridizing to the nucleic acid sequence, or portion thereof, of a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1-268, or portion thereof under stringent conditions as more described above.

To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 80%, or 90% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The invention also encompasses polypeptides having a lower degree of identity but having sufficient similarity so as to perform one or more of the same functions performed by the polypeptide. Similarity is determined by conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in a polypeptide by another amino acid of like characteristics. Conservative substitutions are likely to be phenotypically silent. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr, exchange of the acidic residues Asp and Glu, substitution between the amide residues Asn and Gln, exchange of the basic residues Lys and Arg and replacements among the aromatic residues Phe, Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in Bowie et al., Science 247:1306-1310 (1990).

TABLE 1
Conservative Amino Acid Substitutions.
Aromatic             Phenylalanine
Tryptophan
Tyrosine
Hydrophobic          Leucine
Isoleucine
Valine
Polar                Glutamine
Asparagine
Basic                Arginine
Lysine
Histidine
Acidic               Aspartic Acid
Glutamic Acid
Small                Alanine
Serine
Threonine
Methionine
Glycine

The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished by well-known methods such as using a mathematical algorithm. (Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991).

A preferred, non-limiting example of such a mathematical algorithm is described in Karlin et al., Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) as described in Altschul et al., Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. In one embodiment, parameters for sequence comparison can be set at score=100, wordlength=12, or can be varied (e.g., W=5 or W=20).

In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a BLOSUM 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al., Nucleic Acids Res. 12(1):387 (1984)) (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.

Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the CGC sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Additional algorithms for sequence analysis are known in the art and include ADVANCE and ADAM as described in Torellis and Robotti (1994) Comput. Appl. Biosci. 10:3-5; and FASTA described in Pearson and Lipman (1988) PNAS 85:2444-8.

A variant polypeptide can differ in amino acid sequence by one or more substitutions, deletions, insertions, inversions, fusions, and truncations or a combination of any of these.

Variant polypeptides can be fully functional or can lack function in one or more activities. Thus, in the present case, variations can affect the function, for example, of one or more of the regions corresponding to substrate binding, subcellular localization, such as membrane association, and proteolytic cleavage, effector binding, effector modification of the protease, other modification sites, or site of interaction with any other protein.

Fully functional variants typically contain only conservative variation or variation in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids which result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree.

Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, or truncation or a substitution, insertion, inversion, or deletion in a critical residue or critical region.

As indicated, variants can be naturally-occurring or can be made by recombinant means or chemical synthesis to provide useful and novel characteristics for the protease. This includes preventing immunogenicity from pharmaceutical formulations by preventing protein aggregation.

Useful variations further include alteration of substrate binding and cleavage characteristics. For example, one embodiment involves a variation at the binding site that results in binding but not release, or slower release, of substrate. A further useful variation at the same sites can result in a higher affinity for substrate. Useful variations also include changes that provide for affinity for another substrate. Another useful variation includes one that allows binding but which prevents proteolysis of the substrate. Another useful variation includes variation in the domain that provides for reduced or increased binding by the appropriate activator (effector) or for binding by a different activator than the one with which the protease is normally associated. Another useful variation provides a fusion protein in which one or more domains or subregions is operationally fused to one or more domains or subregions from another protease.

Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as protease binding, cleavage, or in vitro, or in vitro proliferative activity. Sites that are critical for protease binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312 (1992)).

Substantial homology can be to the entire nucleic acid or amino acid sequence or to fragments of these sequences.

The invention also includes polypeptide fragments of the polypeptides of the invention Fragments can be derived from a polypeptide encoded by a nucleic acid comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268 and the complements thereof. However, the invention also encompasses fragments of the variants of the polypeptides encoded by the nucleic acid described herein.

In one embodiment, the fragment is or includes an open reading frame. Open reading frames can be determined by routine computerized homology search procedures.

The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that may be disclosed prior to the present invention.

As used herein, a fragment comprises at least 10 contiguous amino acids. Fragments can retain one or more of the biological activities of the protein, for example the ability to bind to a substrate or activator, as well as fragments that can be used as an immunogen to generate protease antibodies.

Biologically active fragments (peptides which are, for example, 10, 12, 15, 20, 30, 35, 36, 37, 38, 39,40, 50, 100 or more amino acids in length) can comprise a domain or region, as indicated, identified by analysis of the polypeptide sequence by well-known methods, e.g., cleavage sites, substrate binding sites, glycosylation sites, cAMP and cGMP-dependent phosphorylation sites, N-myristoylation sites, activator binding sites, casein kinase II phosphorylation sites, palmitoylation sites, amidation sites, or parts of any of these. Such domains or sites can be identified by means of routine procedures for computerized homology or motif analysis.

Fragments further include combinations of the various functional regions described herein. Other fragments include the mature protein. Fragments, for example, can extend in one or both directions from the functional site to encompass 5, 10, 15, 20, 30, 40, 50, or up to 100 amino acids. Further, fragments can include sub-fragments of the specific domains mentioned above, which sub-fragments retain the function of the domain from which they are derived.

Accordingly, possible fragments include but are not limited to fragments defining a substrate-binding site, fragments defining a phosphorylation site, fragments defining membrane association, fragments defining glycosylation sites, fragments defining interaction with activators and fragments defining myristoylation sites. By this is intended a discrete fragment that provides the relevant function or allows the relevant function to be identified. In a preferred embodiment, the fragment contains the substrate or activator-binding site.

The invention also provides fragments with immunogenic properties. These contain an epitope-bearing portion of the protease and variants. These epitope-bearing peptides are useful to raise antibodies that bind specifically to a protease polypeptide or region or fragment. These peptides can contain at least 10, 12, at least 14, or between at least about 15 to about 30 amino acids.

Non-limiting examples of antigenic polypeptides that can be used to generate antibodies include peptides derived from the amino terminal extracellular domain or any of the extracellular loops. Regions having a high antigenicity index can be determined by routine computerized amino acid sequence analysis. However, intracellularly-made antibodies ("intrabodies") are also encompassed, which would recognize intracellular peptide regions.

The polypeptides (including variants and fragments which may have been disclosed prior to the present invention) are useful for biological assays related to proteases. Such assays involve any of the known protease functions or activities or properties useful for diagnosis and treatment of protease-related conditions.

The epitope-bearing protease and polypeptides may be produced by any conventional means (Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985)). Simultaneous multiple peptide synthesis is described in U.S. Pat. No. 4,631,211.

Fragments can be discrete (not fused to other amino acids or polypeptides) or can be within a larger polypeptide. Further, several fragments can be comprised within a single larger polypeptide. In one embodiment a fragment designed for expression in a host can have heterologous pre- and pro-polypeptide regions fused to the amino terminus of the protease fragment and an additional region fused to the carboxyl terminus of the fragment.

The invention thus provides chimeric or fusion proteins. These comprise a protease amino acid sequence operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the protease. "Operatively linked" indicates that the protease sequence and the heterologous protein are fused in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the protease sequence.

In one embodiment the fusion protein does not affect protease function per se. For example, the fusion protein can be a GST-fusion protein in which the protease sequences are fused to the C-terminus of the GST sequences or an influenza HA marker. Other types of fusion proteins include, but are not limited to, enzymatic fusion proteins, for example beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate the purification of recombinant protease. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Therefore, in another embodiment, the fusion protein contains a heterologous signal sequence at its N-terminus.

EP-A-O 464 533 discloses fusion proteins comprising various portions of immunoglobulin constant regions. The Fc is useful in therapy and diagnosis and thus results, for example, in improved pharmacokinetic properties (EP-A 0232 262). In drug discovery, for example, human proteins have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists. Bennett et al. (J. Mol. Recog. 8:52-58 (1995)) and Johanson et al. (J. Biol. Chem. 270, 16:9459-9471 (1995)). Thus, this invention also encompasses soluble fusion proteins containing a protease polypeptide and various portions of the constant regions of heavy or light chains of immunoglobulins of various subclass (IgG, IgM, IgA, IgE). Preferred as immunoglobulin is the constant part of the heavy chain of human IgG, particularly IgG1, where fusion takes place at the hinge region. For some uses it is desirable to remove the Fc after the fusion protein has been used for its intended purpose, for example when the fusion protein is to be used as antigen for immunizations. In a particular embodiment, the Fc part can be removed in a simple way by a cleavage sequence which is also incorporated and can be cleaved with factor Xa.

A chimeric or fusion protein can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different protein sequences are ligated together in-frame in accordance with conventional techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A protease encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protease sequence.

Another form of fusion protein is one that directly affects protease functions. Accordingly, a polypeptide is encompassed by the present invention in which one or more of the protease domains (or parts thereof) has been replaced by homologous domains (or parts thereof) from another protease or other type of protease. Accordingly, various permutations are possible. The substrate binding, or subregion thereof, can be replaced, for example, with the corresponding domain or subregion from another substrate for the protease. Thus, chimeric proteases can be formed in which one or more of the native domains or subregions has been replaced.

The isolated protease sequence can be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant), or synthesized using known protein synthesis methods.

In one embodiment, the protein is produced by recombinant DNA techniques. For example, a nucleic acid molecule encoding the polypeptide is cloned into an expression vector, the expression vector introduced into a host cell and the protein expressed in the host cell. The protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques.

Polypeptides often contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally-occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Common modifications that occur naturally in polypeptides are described in basic texts, detailed monographs, and the research literature, and they are well known to those of skill in the art.

Accordingly, the polypeptides also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol), or in which the additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

Known modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

Such modifications are well-known to those of skill in the art and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as Proteins--Structure and Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993). Many detailed reviews are available on this subject, such as by Wold, F., Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York 1-12 (1983); Seifter et al. (Meth. Enzymol. 182: 626-646 (1990)) and Rattan et al. (Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

As is also well known, polypeptides are not always entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of post-translation events, including natural processing event and events brought about by human manipulation which do not occur naturally. Circular, branched and branched circular polypeptides may be synthesized by non-translational natural processes and by synthetic methods.

Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. Blockage of the amino or carboxyl group in a polypeptide, or both, by a covalent modification, is common in naturally-occurring and synthetic polypeptides. For instance, the amino terminal residue of polypeptides made in E. coli, prior to proteolytic processing, almost invariably will be N-formylmethionine.

The modifications can be a function of how the protein is made. For recombinant polypeptides, for example, the modifications will be determined by the host cell posttranslational modification capacity and the modification signals in the polypeptide amino acid sequence. Accordingly, when glycosylation is desired, a polypeptide should be expressed in a glycosylating host, generally a eukaryotic cell. Insect cells often carry out the same posttranslational glycosylations as mammalian cells and, for this reason, insect cell expression systems have been developed to efficiently express mammalian proteins having native patterns of glycosylation. Similar considerations apply to other modifications.

The same type of modification may be present in the same or varying degree at several sites in a given polypeptide. Also, a given polypeptide may contain more than one type of modification.

Polypeptide Uses

The protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

The protease polypeptides are useful for producing antibodies specific for the protease, regions, or fragments.

The polypeptides (including variants and fragments which may have been disclosed prior to the present invention) are useful for biological assays related to proteases. Such assays involve any of the known protease functions or activities or properties useful for diagnosis and treatment of protease-related conditions.

The polypeptides are also useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can be native, i.e., cells that normally express the protease protein, as a biopsy or expanded in cell culture. In one embodiment, however, cell-based assays involve recombinant host cells expressing the protease protein.

The polypeptides can be used to identify compounds that modulate protease activity. Such compounds can increase or decrease affinity or rate of binding to a known substrate or activator, compete with substrate or activator for binding to the protease, or displace substrate or activator bound to the protease. Both protease protein and appropriate variants and fragments can be used in high-throughput screens to assay candidate compounds for the ability to bind to the protease. These compounds can be further screened against a functional protease to determine the effect of the compound on the protease activity. Compounds can be identified that activate (agonist) or inactivate (antagonist) the protease to a desired degree. Modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject).

The protease polypeptides can be used to screen a compound for the ability to stimulate or inhibit interaction between the protease protein and a target molecule that normally interacts with the protease protein. The target can be a component of the pathway with which the protease normally interacts. The assay includes the steps of combining the protease with a candidate compound under conditions that allow the protease or fragment to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the protease and the target, such as any of the associated effects of proteolytic cleavage, such as detecting the induction of a reporter gene (comprising a target-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), detecting a cellular response, for example, development, differentiation or rate of proliferation detection of activation of the substrate, or change in substrate levels (i.e., level of end product).

Determining the ability of the protein to bind to a target molecule can also be accomplished using a technology such as real-time Bimolecular Interaction Analysis (BIA). Sjolander, S. and Urbaniczky, C. (1991) Anal. Chem., 63:2338-2345 and Szabo et al. (1995) Curr. Opin. Struct. Biol., 5:699-705. As used herein, "BIA" is a technology for studying biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore™). Changes in the optical phenomenon surface plasmon resonance (SPR) can be used as an indication of real-time reactions between biological molecules.

The test compounds of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the `one-bead one-compound` library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to polypeptide libraries, while the other four approaches are applicable to polypeptide, non-peptide oligomer or small molecule libraries of compounds (Lam, K. S. (1997) Anticancer Drug Des. 12:145).

Examples of methods for the synthesis of molecular libraries can be found in the art, for example in DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A., 90:6909; Erb et al. (1994) Proc. Natl Acad. Sci. U.S.A., 91:11422; Zuckermann et al. (1994). J. Med. Chem., 37:2678; Cho et al.(1993) Science, 261:1303; Carell et al. (1994) Angew. Chem. Int. Ed. Engl., 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl., 33:2061; and in Gallop et al. (1994) J. Med. Chem., 37:1233.

Libraries of compounds may be presented in solution (e.g., Houghten (1992) Biotechniques, 13:412-421), or on beads (Lam(1991) Nature, 354:82-84), chips (Fodor (1993) Nature, 364;555-556), bacteria(Ladner U.S. Pat. No. 5,223,409), spores (Ladner U.S. Pat. No. '409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. U.S.A., 89:1865-1869) or on phage (Scott and Smith (1990) Science, 249:386-390); (Devlin (1990) Science, 249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci., 97:6378-6382); (Felici (1991) J. Mol. Biol., 222:301-310); (Ladner supra).

Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab')₂, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

One candidate compound is a soluble full-length protease or fragment that competes for substrate or activator binding. Other candidate compounds include mutant proteases or appropriate fragments containing mutations that affect protease function and thus compete for substrate, activator or other protein that interacts with the protease. Accordingly, a fragment that competes for substrate or activator, for example with a higher affinity, or a fragment that binds substrate or activator but does not allow release, is encompassed by the invention.

The invention provides other end points to identify compounds that modulate (stimulate or inhibit) protease activity. The assays typically involve an assay of events in the pathway in which the protease is found that indicate protease activity. Thus, the expression of genes that are up- or down-regulated in response to the protease protein dependent cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, modification of the protease protein, or a protease protein target, could also be measured.

Any of the biological or biochemical functions mediated by the protease can be used as an endpoint assay. These include all of the biochemical or biochemical/biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.

Binding and/or activating compounds can also be screened by using chimeric proteases in which a domain, or parts thereof, are replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is recognized by the native protease. Accordingly, a different set of pathway components is available as an end-point assay for activation. Alternatively, a portion or subregions can be replaced with a portion or subregions specific to a host cell that is different from the host cell from which the domain is derived. This allows for assays to be performed in other than the specific host cell from which the protease is derived. Alternatively, the substrate or activator could be replaced by a domain (and/or other binding region) binding a different substrate or activator, thus providing an assay for test compounds that interact with the heterologous domain (or region) but still cause the events in the pathway. Finally, activation can be detected by a reporter gene containing an easily detectable coding region operably linked to a transcriptional regulatory sequence that is part of the native signal transduction pathway.

The protease polypeptides are also useful in competition binding assays in methods designed to discover compounds that interact with the protease. Thus, a compound is exposed to a protease polypeptide under conditions that allow the compound to bind or to otherwise interact with the polypeptide. Soluble polypeptide is also added to the mixture. If the test compound interacts with the soluble polypeptide, it decreases the amount of complex formed or activity from the protease target. This type of assay is particularly useful in cases in which compounds are sought that interact with specific regions of the protease. Thus, the soluble polypeptide that competes with the target protease region is designed to contain peptide sequences corresponding to the region of interest.

Determining the ability of the test compound to interact with the polypeptide can also comprise determining the ability of the test compound to preferentially bind to the polypeptide as compared to the ability of the native counterpart, such as activator or substrate, or a biologically active portion thereof, to bind to the polypeptide.

To perform cell free drug screening assays, it is desirable to immobilize either the protease, or fragment, or its target molecule to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay.

Techniques for immobilizing proteins on matrices can be used in the drug screening assays. In one embodiment, a fusion protein can be provided which adds a domain that allows the protein to be bound to a matrix. For example, glutathione-S-transferase/protease fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., ³5 S-labeled) and the candidate compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads are washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of protease-binding protein found in the bead fraction quantitated from the gel using standard electrophoretic techniques. For example, either the polypeptide or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin using techniques well known in the art. Alternatively, antibodies reactive with the protein but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and the protein trapped in the wells by antibody conjugation. Preparations of a protease-binding protein and a candidate compound are incubated in the protease protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protease protein target molecule, or which are reactive with protease protein and compete with the target molecule; as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

Modulators of protease activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protease pathway, by treating cells that express the protease. These methods of treatment include the steps of administering the modulators of protein activity in a pharmaceutical composition as described herein, to a subject in need of such treatment. The compounds may be tested first in an animal model to determine safety and efficacy.

The protease polypeptides are thus useful for treating a protease-associated disorder characterized by aberrant expression or activity of a protease. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., upregulates or downregulates) expression or activity of the protein. In another embodiment, the method involves administering a protein as therapy to compensate for reduced or aberrant expression or activity of the protein. Accordingly, methods for treatment include the use of soluble protease or fragments of the protease protein that compete, for example, with activator or substrate binding. These proteases or fragments can have a higher affinity for the activator or substrate so as to provide effective competition.

Stimulation of protein activity is desirable in situations in which the protein is abnormally downregulated and/or in which increased protein activity is likely to have a beneficial effect. Likewise, inhibition of protein activity is desirable in situations in which the protein is abnormally upregulated and/or in which decreased protein activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant development or cellular differentiation. Another example of such a situation is where the subject has a proliferative disease (e.g., cancer) or a disorder characterized by an aberrant hematopoietic response. Yet another example of such a situation is where it is desirable to achieve tissue regeneration in a subject (e.g., where a subject has undergone brain or spinal cord injury and it is desirable to regenerate neuronal tissue in a regulated manner).

In yet another aspect of the invention, the proteins of the invention can be used as "bait proteins" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell, 72:223-232; Madura et al. (1993) J. Biol. Chem., 268:12046-12054; Bartel et al. (1993) Biotechniques, 14:920-924; Iwabuchi et al. (1993) Oncogene, 8:1693-1696; and Brent WO94/10300), to identify other proteins (captured proteins) which bind to or interact with the proteins of the invention and modulate their activity. Such captured proteins are also likely to be involved in the pathway that includes by the proteins of the invention as, for example, downstream elements of a protease-mediated pathway.

The protease polypeptides also are useful to provide a target for diagnosing a disease or predisposition to disease mediated by the protease, such as a proliferative disorder, a differentiative or developmental disorder, or a hematopoietic disorder. Accordingly, methods are provided for detecting the presence, or levels of the protease in a cell, tissue, or organism. The method can involve contacting a biological sample with a compound capable of interacting with the protease such that the interaction can be detected.

One agent for detecting a protease is an antibody capable of selectively binding to the protease. A biological sample includes tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

The protease also provides a target for diagnosing active disease, or predisposition to disease, in a patient having a variant protease. Thus, protease can be isolated from a biological sample, assayed for the presence of a genetic mutation that results in aberrant protease. This includes amino acid substitution, deletion, insertion, rearrangement, (as the result of aberrant splicing events), and inappropriate post-translational modification. Analytic methods include altered electrophoretic mobility, altered tryptic peptide digest, altered protease activity in cell-based or cell-free assay, alteration in activator, substrate, or antibody-binding pattern, altered isoelectric point, direct amino acid sequencing, and any other of the known assay techniques useful for detecting mutations in a protein.

In vitro techniques for detection of protease include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. Alternatively, the protein can be detected in vivo in a subject by introducing into the subject a labeled anti-protease antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. Particularly useful are methods which detect the allelic variant of a protease expressed in a subject and methods which detect fragments of a protease in a sample.

It is also within the scope of this invention to determine the ability of a test compound to interact with the polypeptide without the labeling of any of the interactants. For example, a microphysiometer can be used to detect the interaction of a test compound with the polypeptide without the labeling of either the test compound or the polypeptide. McConnell, H. M. et al. (1992) Science, 257:1906-1912.

The present invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant expression or activity of proteins of the invention. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression.

With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. The polypeptides thus provide a target to ascertain a genetic predisposition that can affect treatment modality. Thus, in a substrate-based treatment, polymorphism may give rise to substrate or activator-binding regions that are more or less active in substrate or activator binding, and protease activation or proteolysis. Accordingly, activator or substrate dosage would necessarily be modified to maximize the therapeutic effect within a given population containing a polymorphism. As an alternative to genotyping, specific polymorphic polypeptides could be identified.

The protease polypeptides are also useful for monitoring therapeutic effects during clinical trials and other treatment. Thus, the therapeutic effectiveness of an agent that is designed to increase or decrease gene expression, protein levels or protease activity can be monitored over the course of treatment using the polypeptides as an end-point target. The monitoring can be, for example, as follows: (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a specified protein in the pre-administration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the protein in the post-administration samples; (v) comparing the level of expression or activity of the protein in the pre-administration sample with the protein in the post-administration sample or samples; and (vi) increasing or decreasing the administration of the agent to the subject accordingly.

The invention also comprises kits for detecting a protease protein. The kit can comprise a labeled compound or agent capable of detecting protein in a biological sample, such as an antibody or other binding compound; means for determining the amount of in the sample; and means for comparing the amount of in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect the protein.

Antibodies

In another aspect, the invention provides antibodies to the polypeptides and polypeptide fragments of the invention, e.g., having an amino acid encoded by a nucleic acid comprising all or a portion of a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-268. Antibodies selectively bind to the protease and its variants and fragments. An antibody is considered to selectively bind, even if it also binds to other proteins that are not substantially homologous with the protease. These other proteins share homology with a fragment or domain of the protease. This conservation in specific regions gives rise to antibodies that bind to both proteins by virtue of the homologous sequence. In this case, it would be understood that antibody binding to the protease is still selective.

To generate antibodies, an isolated protease polypeptide is used as an immunogen to generate antibodies using standard techniques for polyclonal and monoclonal antibody preparation. Either the full-length protein or an antigenic peptide fragment can be used.

Antibodies are preferably prepared from these regions or from discrete fragments in antigenic regions. However, antibodies can be prepared from any region of the peptide as described herein. A preferred fragment produces an antibody that diminishes or completely prevents substrate or activator-binding. Antibodies can be developed against the entire protease or portions of the protease, for example, specific segments or any portions thereof. Antibodies may also be developed against specific functional sites, such as the site of substrate or activator-binding, or sites that are phosphorylated, glycosylated, myristoylated, or otherwise modified, such as amidated.

An antigenic fragment will typically comprise at least 10 contiguous amino acid residues. The antigenic peptide can comprise, however, at least 12, at least 14 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, or at least 30 amino acid residues. In one embodiment, fragments correspond to regions that are located on the surface of the protein, e.g., hydrophilic regions. These fragments are not to be construed, however, as encompassing any fragments which may be disclosed prior to the invention.

Antibodies can be polyclonal or monoclonal. An intact antibody, or a fragment thereof (e.g. Fab or F(ab')₂) can be used.

Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody to a polypeptide of the invention.

Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹25 I, ¹31 I, ³5 S or ³ H.

An appropriate immunogenic preparation can be derived from native, recombinantly expressed, protein or chemically synthesized peptides.

Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., U.S. Pat. Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, Calif.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

Completely human antibodies that recognize a selected epitope can be generated using a technique referred to as "guided selection." This technology is described, for example, in Jespers et al. (1994, Bio/technology 12:899-903).

Antibody Uses

The antibodies can be used to isolate a protease by standard techniques, such as affinity chromatography or immunoprecipitation. The antibodies can facilitate the purification of the natural protease from cells and recombinantly produced protease expressed in host cells.

The antibodies are useful to detect the presence of a protease in cells or tissues to determine the pattern of expression of the protease among various tissues in an organism and over the course of normal development.

The antibodies can be used to detect a protease in situ, in vitro, or in a cell lysate or supernatant in order to evaluate the abundance and pattern of expression.

The antibodies can be used to assess abnormal tissue distribution or abnormal expression during development.

Antibody detection of circulating fragments of the full length protease can be used to identify protease turnover.

Further, the antibodies can be used to assess protease expression in disease states such as in active stages of the disease or in an individual with a predisposition toward disease related to protease function. When a disorder is caused by an inappropriate tissue distribution, developmental expression, or level of expression of the protease protein, the antibody can be prepared against the normal protease. If a disorder is characterized by a specific mutation in the protease, antibodies specific for this mutant protein can be used to assay for the presence of the specific mutant protease. However, intracellularly-made antibodies ("intrabodies") are also encompassed, which would recognize intracellular protease peptide regions.

The antibodies can also be used to assess normal and aberrant subcellular localization of cells in the various tissues in an organism. Antibodies can be developed against the whole protease or portions of the protease, such as those described herein.

The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting protease expression level or the presence of aberrant proteases and aberrant tissue distribution or developmental expression, antibodies directed against the protease or relevant fragments can be used to monitor therapeutic efficacy.

Antibodies accordingly can be used diagnostically to monitor levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen.

Additionally, antibodies are useful in pharmacogenomic analysis. Thus, antibodies prepared against polymorphic proteases can be used to identify individuals that require modified treatment modalities.

The antibodies are also useful as diagnostic tools as an immunological marker for aberrant protease analyzed by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays known to those in the art.

The antibodies are also useful for tissue typing. Thus, where a specific protease has been correlated with expression in a specific tissue, antibodies that are specific for this protease can be used to identify a tissue type.

The antibodies are also useful in forensic identification. Accordingly, where an individual has been correlated with a specific genetic polymorphism resulting in a specific polymorphic protein, an antibody specific for the polymorphic protein can be used as an aid in identification.

The antibodies are also useful for inhibiting protease function, for example, blocking substrate or activator binding.

These uses can also be applied in a therapeutic context in which treatment involves inhibiting protease function. An antibody can be used, for example, to block activator or substrate binding. Antibodies can be prepared against specific fragments containing sites required for function or against intact protease associated with a cell.

The invention also encompasses kits for using antibodies to detect the presence of a protease in a biological sample. The kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting protease in a biological sample; means for determining the amount of protease in the sample; and means for comparing the amount of protease in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect protease.

Computer Readable Means

The nucleotide or amino acid sequences of the invention are also provided in a variety of mediums to facilitate use thereof. As used herein, "provided" refers to a manufacture, other than an isolated nucleic acid or amino acid molecule, which contains a nucleotide or amino acid sequence of the present invention. Such a manufacture provides the nucleotide or amino acid sequences, or a subset thereof (e.g., a subset of open reading frames (ORFs)) in a form which allows a skilled artisan to examine the manufacture using means not directly applicable to examining the nucleotide or amino acid sequences, or a subset thereof, as they exists in nature or in purified form.

In one application of this embodiment, a nucleotide or amino acid sequence of the present invention can be recorded on computer readable media. As used herein, "computer readable media" refers to any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. The skilled artisan will readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide or amino acid sequence of the present invention.

As used herein, "recorded" refers to a process for storing information on computer readable medium. The skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide or amino acid sequence information of the present invention.

A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide or amino acid sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MicroSoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. The skilled artisan can readily adapt any number of dataprocessor structuring formats (e.g., text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.

By providing the nucleotide or amino acid sequences of the invention in computer readable form, the skilled artisan can routinely access the sequence information for a variety of purposes. For example, one skilled in the art can use the nucleotide or amino acid sequences of the invention in computer readable form to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of the sequences of the invention which match a particular target sequence or target motif.

As used herein, a "target sequence" can be any DNA or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 100 amino acids or from about 30 to 300 nucleotide residues. However, it is well recognized that commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.

As used herein, "a target structural motif," or "target motif," refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).

Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium for analysis and comparison to other sequences. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to, MacPattern (EMBL), BLASTN and BLASTX (NCBIA).

For example, software which implements the BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system can be used to identify open reading frames (ORFs) of the sequences of the invention which contain homology to ORFs or proteins from other libraries. Such ORFs are protein encoding fragments and are useful in producing commercially important proteins such as enzymes used in various reactions and in the production of commercially useful metabolites.

Vectors/Host Cells

The invention thus provides vectors containing the protease polynucleotides. Another aspect of the invention pertains to nucleic acid constructs containing a nucleic acid selected from the group consisting of SEQ ID NOS: 1-268 (or a portion thereof). The term "vector" refers to a vehicle, preferably a nucleic acid molecule, that can transport the protease polynucleotides. When the vector is a nucleic acid molecule, the protease polynucleotides are covalently linked to the vector nucleic acid. With this aspect of the invention, the vector includes a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, OR MAC.

A vector can be maintained in the host cell as an extrachromosomal element where it replicates and produces additional copies of the protease polynucleotides. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the protease polynucleotides when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the protease polynucleotides. The vectors can function in procaryotic or eukaryotic cells or in both (shuttle vectors).

Expression vectors contain cis-acting regulatory regions that are operably linked in the vector to the protease polynucleotides such that transcription of the polynucleotides is allowed in a host cell. Within a recombinant expression vector, "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The polynucleotides can be introduced into the host cell with a separate polynucleotide capable of affecting transcription. Thus, the second polynucleotide may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the protease polynucleotides from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself.

It is understood, however, that in some embodiments, transcription and/or translation of the protease polynucleotides can occur in a cell-free system.

The regulatory sequence to which the polynucleotides described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region a ribosome binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. The person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. Such regulatory sequences are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual. 2nd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989), and such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990).

A variety of expression vectors can be used to express a protease polynucleotide. Such vectors include chromosomal, episomal, and virus-derived vectors, for example vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, adeno-associated virus, poxviruses, pseudorabies viruses, and retroviruses. Vectors may also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g,. cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook et al., Molecular Cloning: A Laboratory Manual. 2nd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989).

The regulatory sequence may provide constitutive expression in one or more host cells (i.e. tissue specific) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor such as a hormone or other ligand. A variety of vectors providing for constitutive and inducible expression in prokaryotic and eukaryotic hosts are well known to those of ordinary skill in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et al. (1987) Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto and Baltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Banerji et al. (1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund et al. (1985) Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss (1990) Science 249:374-379) and the α-fetoprotein promoter (Campes and Tilghman (1989) Genes Dev. 3:537-546). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

The protease polynucleotides can be inserted into the vector nucleic acid by well-known methodology. Generally, the DNA sequence that will ultimately be expressed is joined to an expression vector by cleaving the DNA sequence and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

The vector containing the appropriate polynucleotide can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial cells include, but are not limited to, E. coli, Streptomyces, and Salmonella typhimurium. Eukaryotic cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells, and plant cells.

As described herein, it may be desirable to express the polypeptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the protease polypeptides. Fusion vectors can increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting for example as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired polypeptide can ultimately be separated from the fusion moiety. Proteolytic enzymes include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a host bacteria by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein. (Gottesman, S., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990) 119-128). Alternatively, the sequence of the polynucleotide of interest can be altered to provide preferential codon usage for a specific host cell, for example E. coli. (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

The protease polynucleotides can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast e.g., S. cerevisiae include pYepSec1 (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (Kujan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

The protease polynucleotides can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol. Cell Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).

In certain embodiments of the invention, the polynucleotides described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B. Nature 329:840 (1987)) and pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook et al, supra.

Suitable host cells are discussed further in Goeddel, supra. Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

It is understood that "host cells" and "recombinant host cells" refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

The expression vectors listed herein are provided by way of example only of the well-known vectors available to those of ordinary skill in the art that would be useful to express the protease polynucleotides. The person of ordinary skill in the art would be aware of other vectors suitable for maintenance propagation or expression of the polynucleotides described herein. These are found for example in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

The invention also encompasses vectors in which the nucleic acid sequences described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to all, or to a portion, of the polynucleotide sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as plant, fungal, and insect cells, and higher eukaryotic cells such as mammalian cells.

The recombinant host cells are prepared by introducing the vector constructs described herein into the cells by techniques readily available to the person of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).

Host cells can contain more than one vector. Thus, different nucleotide sequences can be introduced on different vectors of the same cell. Similarly, the protease polynucleotides can be introduced either alone or with other polynucleotides that are not related to the protease polynucleotides such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced or joined to the protease polynucleotide vector.

In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication will occur in host cells providing functions that complement the defects.

Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be contained in the same vector that contains the polynucleotides described herein or may be on a separate vector. Markers include tetracycline or ampicillin-resistance genes for prokaryotic host cells and dihydrofolate reductase or neomycin resistance for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait will be effective.

While the mature proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these proteins using RNA derived from the DNA constructs described herein.

Where secretion of the polypeptide is desired, appropriate secretion signals are incorporated into the vector. The signal sequence can be endogenous to the protease polypeptides or heterologous to these polypeptides.

Where the polypeptide is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze thaw, sonication, mechanical disruption, use of lysing agents and the like. The polypeptide can then be recovered and purified by well-known purification methods including ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

It is also understood that depending upon the host cell in recombinant production of the polypeptides described herein, the polypeptides can have various glycosylation patterns, depending upon the cell, or maybe non-glycosylated as when produced in bacteria. In addition, the polypeptides may include an initial modified methionine in some cases as a result of a host-mediated process.

Uses of Vectors and Host Cells

The host cells expressing the polypeptides described herein, and particularly recombinant host cells, have a variety of uses. First, the cells are useful for producing protease polypeptides that can be further purified to produce desired amounts of these. Thus, host cells containing expression vectors are useful for polypeptide production.

Host cells are also useful for conducting cell-based assays involving the protease or protease fragments. Thus, a recombinant host cell expressing a native protease is useful to assay for compounds that stimulate or inhibit protease function. This includes activator binding, gene expression at the level of transcription or translation, substrate interaction, and components of the pathway in which the protease is a member.

Host cells are also useful for identifying protease mutants in which these functions are affected. If the mutants naturally occur and give rise to a pathology, host cells containing the mutations are useful to assay compounds that have a desired effect on the mutant protease (for example, stimulating or inhibiting function) which may not be indicated by their effect on the native protease.

Recombinant host cells are also useful for expressing the chimeric polypeptides described herein to assess compounds that activate or suppress activation by means of a heterologous activator binding domain. Alternatively, a heterologous proteolytic region can be used to assess the effect of a desired proteolytic domain on any given host cell. In this embodiment, a proteolytic region (or parts thereof) compatible with the specific host cell is used to make the chimeric vector. Alternatively, a heterologous substrate binding domain can be introduced into the host cell.

Further, mutant proteases can be designed in which one or more of the various functions is engineered to be increased or decreased (e.g., activator binding or substrate binding) and used to augment or replace proteases in an individual. Thus, host cells can provide a therapeutic benefit by replacing an aberrant protease or providing an aberrant protease that provides a therapeutic result. In one embodiment, the cells provide proteases that are abnormally active.

In another embodiment, the cells provide proteases that are abnormally inactive. These proteases can compete with endogenous proteases in the individual.

In another embodiment, cells expressing proteases that cannot be activated, are introduced into an individual in order to compete with endogenous proteases for activator. For example, in the case in which excessive activator is part of a treatment modality, it may be necessary to inactivate this activator at a specific point in treatment. Providing cells that compete for the activator, but which cannot be affected by protease activation would be beneficial.

Homologously recombinant host cells can also be produced that allow the in situ alteration of endogenous protease polynucleotide sequences in a host cell genome. This technology is more fully described in WO 93/09222, WO 91/12650 and U.S. Pat. No. 5,641,670. Briefly, specific polynucleotide sequences corresponding to the protease polynucleotides or sequences proximal or distal to a protease gene are allowed to integrate into a host cell genome by homologous recombination where expression of the gene can be affected. In one embodiment, regulatory sequences are introduced that either increase or decrease expression of an endogenous sequence. Accordingly, a protease can be produced in a cell not normally producing it, or increased expression of protease can result in a cell normally producing the protein at a specific level. Alternatively, the entire gene can be deleted. Still further, specific mutations can be introduced into any desired region of the gene to produce mutant proteases. Such mutations could be introduced, for example, into the specific functional regions.

In one embodiment, the host cell can be a fertilized oocyte or embryonic stem cell that can be used to produce a transgenic animal containing the altered protease gene. Alternatively, the host cell can be a stem cell or other early tissue precursor that gives rise to a specific subset of cells and can be used to produce transgenic tissues in an animal. See also Thomas et al., Cell 51:503 (1987) for a description of homologous recombination vectors. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced gene has homologously recombined with the endogenous protease gene is selected (see e.g., Li, E. et al., Cell 69:915 (1992)). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see e.g., Bradley, A. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987) pp. 113-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, A. (1991) Current Opinion in Biotechnology 2:823-829 and in PCT International Publication Nos. WO 90/11354; WO 91/01140; and WO 93/04169.

The genetically engineered host cells can be used to produce non-human transgenic animals. A transgenic animal is preferably a mammal, for example a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more cell types or tissues of the transgenic animal. These animals are useful for studying the function of a protease protein and identifying and evaluating modulators of protease protein activity.

Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, and amphibians.

In one embodiment, a host cell is a fertilized oocyte or an embryonic stem cell into which protease polynucleotide sequences have been introduced.

A transgenic animal can be produced by introducing nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any of the protease nucleotide sequences can be introduced as a transgene into the genome of a non-human animal, such as a mouse.

Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the protease to particular cells.

Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al. and in Hogan, B., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes animals in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

In another embodiment, transgenic non-human animals can be produced which contain selected systems which allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae (O'Gorman et al. Science 251:1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein is required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, I. et al. Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell, e.g., a somatic cell, from the transgenic animal can be isolated and induced to exit the growth cycle and enter G_o phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to a pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell, e.g., the somatic cell, is isolated.

Transgenic animals containing recombinant cells that express the polypeptides described herein are useful to conduct the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could affect binding, protease activation, and the pathway events may not be evident from in vitro cell-free or cell-based assays. Accordingly, it is useful to provide non-human transgenic animals to assay in vivo protease function, including substrate or activator interaction, the effect of specific mutant proteases on protease function and interaction with other components, and the effect of chimeric proteases. It is also possible to assess the effect of null mutations, that is mutations that substantially or completely eliminate one or more protease functions.

Pharmaceutical Compositions

The protease nucleic acid molecules, protein (particularly fragments that comprise an extracellular domain), modulators of the protein, and antibodies (also referred to herein as "active compounds") can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically comprise the nucleic acid molecule, protein, modulator, or antibody and a pharmaceutically acceptable carrier.

As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, such media can be used in the compositions of the invention. Supplementary active compounds can also be incorporated into the compositions. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a protease or anti-protease antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration, the agent can be contained in enteric forms to survive the stomach or further coated or mixed to be released in a particular region of the GI tract by known methods. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470) or by stereotactic injection (see e.g., Chen et al., PNAS 91:3054-3057 (1994)). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g. retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

This invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will fully convey the invention to those skilled in the art. Many modifications and other embodiments of the invention will come to mind in one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing description. Although specific terms are employed, they are used as in the art unless otherwise indicated.

SEQUENCE LISTING
<100> GENERAL INFORMATION:
<160> NUMBER OF SEQ ID NOS: 268
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 1
<211> LENGTH: 1504
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  1
tcatttaggg atcgacgccc gcgtccgcgg acgcgtgggc ggacgcgtgg gcggacgcgt     60
gggtggttat aactcaggcc cggtgcccag agcccaggag gaggcagtgg ccaggaaggc    120
acaggcctga gaagtctgcg gctgagctgg gagcaaatcc cccaccccct acctggggga    180
caggtgcctg ggtctcagcg cagtgccgat ggtggcccgt ccttgtggtt cctctctacc    240
tgggggacag ggcaagtgag acctggtgca gcggccatgg ctacagcaag acccccctgg    300
atgtgggtgc tctgtgctct gatcacagcc ttgcttctgg gggtcacaga gcatgttttc    360
gccaaacaat gatgtttcct gtgaccaccc ctctaacacc cgtgccctct gggagcaaac    420
caggacttgg ggaactgggg cccggggaag aacgcccggt cggatgacag cagcagcccg    480
catcatcaat ggatccgaac tgcgatatgc acacccagcc gtggcaggcc cgcgctgttg    540
ttaaaggccc caaccaagtt cttattgcgg ggcggtgttg gtgcatccac agtggtggtt    600
cacggccgcc ccactgcagg aagaaagttt tcagagtccg tctcggccac tattccctgt    660
caccagttta tgaatctggg cagcaagatg ttccaggggg tcaaatccat cccccaccct    720
ggctactccc accctggcca ctctaacgac ctcatgctca tcaaactgaa cagaagaatt    780
cgtcccacta aagatgtcag acccatcaac gtctcctctc attgtccctc tgctgggaca    840
aagtgcttgg tgtctggctg ggggacaacc aagagccccc aagtgcactt ccctaaggtc    900
ctccagtgct tgaatatcag cgtgctaagt cagaaaaggt gcgaggatgc ttacccgaga    960
cagatagatg acaccatgtt ctgcgccggt gacaaagcag gtagagactc ctgccagggt   1020
gattctgggg ggcctgtggt ctgcaatggc tccctgcagg gactcgtgtc ctgggggaga   1080
ttacccttgt gcccggccca acagaccggg tgtctacacg aacctctgca agttcaccaa   1140
gtggatccag gaaaccatcc aggccaactc ctgagtcatc ccaggactca gcacaccggc   1200
atccccacct gctgcaggga cagccctgac actcctttca gaccctcatt ccttcccaga   1260
gatgttgaga atgttcatct ctccagcccc tgaccccatg tctcctggac tcagggtctg   1320
cttcccccac attgggctga ccgtgtctct ctagttgaac cctgggaaca atttccaaaa   1380
ctgtccaggg cgggggttgc gtctcaatct ccctggggca ctttcatcct caagctcagg   1440
gcccatccct tctctgcagc tctgacccaa atttagtccc cagaaataaa ctgagaagtg   1500
gaat                                                                1504
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 2
<211> LENGTH: 328
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  2
cttatctccc catgcccaaa gtttgcctgt tccataacac tcactccctt cccccttgct     60
aatcagaagc catctcctct cagtgtctga tctctgctct tcatacatga ttacagtcat    120
ggggtagaga gtgcttgcta aattatgcag ttaatcctat ggtgctttaa ttttcaggcc    180
ttcaaaaaac acttgtacag tgatgtgcag atttttaaac agttgaactt ccttgtacta    240
cagtttttgt attgacagcc aaatttgtct ttcattcttc agattgtgaa taaagtgatt    300
tttacagggc ttccagcaaa gtttttcc                                       328
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 3
<211> LENGTH: 618
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  3
gcggctactc tgtggggcga cctcatcgcc tcagatggct cctgacagca gcccactgcc     60
tcaagccccg ctacatagtt cacctggggc agcacaacct ccagaaggag gagggctgtg    120
agcagacccg gacagccact gagtccttcc cccaccccgg cttcaacaac agcctcccca    180
acaaagacca ccgcaatgac atcatgctgg tgaagatggc atcgccagtg ctccatcacc    240
tgggctgtgc gacccctcac cctctcctca tgctgtgtca ctgctggcac cagctgcctc    300
atttccggct ggggcagcac gtccagcccc cagttacgcc tgcctcacac cttgcgatgc    360
gccaacatca ccatcattga gcaccagaag tgtgagaacg cctaccccgg caacatcaca    420
gacaccatgg tgtgtgccag cgtgaaggaa gggggcaagg actcctgcca agtctcttca    480
aaggcattat ctcctggggg ccaggactcc gtgtgcgatc acccgaaagc ctggtgtcta    540
cacgaaagtc tgcaaatatg tggactggat ccaggaagac gattgaagaa caattagact    600
ggacccaacc aacaaagg                                                  618
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 4
<211> LENGTH: 840
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  4
actactatag ggagtcgacc ccgcgtccgc ggacgcgtgg gctagaacac tcagctgctt     60
ctttggtcat ccttgttttc taactttatg aactccctct gtgtcactgt atgtgaaagg    120
aaatgcacca acaaccgaaa actgaacgtg ttcttttgtg ctcttttata acttgcatta    180
catgttgtaa gcatggtccg ttctatacct ttttctggtc ataatgaaca ctcattttgt    240
tagcgagggt ggtaaaagtt gaacaaaaag gggaagtatc aaactactgc catttcagtg    300
agaaaatcct aggtgctact ttataataag acatttgtta ggccattctt gcattgatat    360
aaagaaatac ctgagactgg gtaatttata aagaaaagag gtttaattgg ctcacaagtt    420
ctgcaggctg tacaggaaac atggctgggg aggcctcagg aaacttacac tcatggcaga    480
aggggaagca aacacatcct tcttcacagg gtggcaggag agagaagaat gagagtgagg    540
ggggtgaaag ccctttataa aatcgtcaga tttcatgaga actcattccc tgtcatgagt    600
acagcatgag ggtaaccgcc cccatgattc agttacttcc ctccaggtcc ctcccataac    660
acatggggat tatgggaact acagttcaat atgagatttg gatggggaca cacccaaacc    720
acatcaccgc cttatctggt gattttgctt tctgcagttt cagttaccct tggtcaaccg    780
ttggttcaaa aatattcaat gggaaaattc cagaaacaat ttcctaagtt ctaaatttca    840
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 5
<211> LENGTH: 559
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  5
tttttttttt ttttcaaaaa ggcaactttt ttttttttct tggcatcaat gaatatgcac     60
ttcanaaatc tacagagaac ttttttcact tnggntttgt tccacagcat tctagccagg    120
agtacaaaat aggagctctt caagcagcac atgaagatgg cccaggagcc ttcagccatc    180
cagagcagca nagcagcacc taaatctcca cacacttccc agtntaacca ctaanaacac    240
actagaccct tggcattagg ggatttatca tttccagttc tattatctgg gaatgactcc    300
aagggtttgt gacaagcttt tgaaacgtaa gtgctaanac gagtgtggac aagtcactga    360
gctaatgaan aatagaccca ctgtctgctt ggctctgcta ttttgtacct gtcttcacat    420
gtggggaaac ttcataactg tgcccacaaa tcagagaaat tcgcaaagga ctagacaatg    480
tattgcctgt gaacttcaga ggcaactgga aatagtgcaa ctggaaatca actagcttca    540
tacataggcg gatttgttt                                                 559
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 6
<211> LENGTH: 216
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  6
tcgcagctgc agccaaatca taaacggcga ggactgcagc ccgcactcgc agccctggca     60
ggcggcactg gtcatggaaa acgaattntt ctgctcgggc gtcctggtgc atccgcagtg    120
ggtgctgtna gccgcacact gtttccagaa ctcctacacc atcgggctgg gcctncacag    180
tnttnaggcc gaccaagagc cagggagcca gatggt                              216
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 7
<211> LENGTH: 576
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  7
gccgactact actactacta ctactaaatt cgcggccggt cgaccagaag gactcctgca     60
acggtgactc ctgtggggcc cctgatctgc aacgggtact tgcagggcct tgtgtctttc    120
ggaaaagccc cgtgtggcca agttggcgtg ccaggtgtct acaccaacct ctgcaaattc    180
actgagtgga tagagaaaac cgtccaggcc agttaactct ggggactggg aacccatgaa    240
attgaccccc aaatacatcc tgcggaagga attcaggaat atctgttccc agcccctcct    300
ccctcaggcc caggagtcca gatccccaga aactacttcc ttcaacccag gttacagatt    360
cccaaaggac acttacatca ggaccaagga gtacacgatc aanaaacana nnnnnggcca    420
aagaacacag taaggacaaa gtcacgaaat ggccgatgta cgcagtaaag aaaattttgc    480
gccactctcg nnaggagcaa ggagcgaaac acagaggaga gatgagtcca gcgcgccagg    540
agacaccgta tggcntgaga gaacaatatt acgaga                              576
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 8
<211> LENGTH: 428
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  8
ccgggtnttg gggaagggtg ggantgggga ccanagtgct gtacggtgct gtgggatctg     60
cagatgaagc ggtgggggct aaggaaaggt cccctggccg ccacttccca gcagcgcctc    120
tcccaggtcc cccagtcctg ctccctgctg agacccacct ctgatccatg attccccttc    180
attgccccca tactttgcat ctcacnaaag gccaggggag cacatacatc ccgaaaaggg    240
cnngtccctn ttnaaatgaa caacctanaa cccggtcacg cctggcacca tgtccctcan    300
attactnccc cacnattatt cagggacttg cccatnactg gctctnccct ttattcnact    360
cccnnatcan atcttgagac catnngacct ggaatcaccc cacnaaacan tttcctgaaa    420
tattccac                                                             428
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 9
<211> LENGTH: 678
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  9
cggggaanga gtcnaagttc aacnggagcg cccanctttg gggccgnnag caggtnaang     60
natggtttcc agcnccggtc ggcagttttn gtttcgcccn aatttnggga ntggtnactt    120
cagcaacaat tcagtttgca cccgngccag tttttccaag agtttnggca gnacttggcg    180
gtcaaacagg tnttcttcna gtgcttaaca atgatcttnt cntccaccga gtgtgtcttt    240
aacatttatt gacggggttt cccacaggtc cgcagtcaaa gaatcgctga accgcgtttc    300
ctcgagagac ggtgtgtggc atgggcgcct tgctgctgcc ccagtcccag agcttctcct    360
gtaggggtgt cggctacagg aaccttatcc cagctccaaa ctggacgcca tcacatatcc    420
tgtcgcctgt ctgtactccc atggggacgc agtaattaag ttccaaccga gcgatgttgc    480
caagcctgag gacaatcccg gccccgtacg accagcggat gaactcagcc agcttaccga    540
atatgagctt ttggggccct ccccataagt tgaggtttca gaggtttcct gcgttgagaa    600
agaagtgtgt tcggaaaaag ttctcccaaa gccaccctgg gctggccgga aaangtaatg    660
ggggtgtaga aggtgcan                                                  678
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 10
<211> LENGTH: 1553
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  10
tccgatgnga agtgcctntc gaaaagccag cagtgcaatg ggaaggacga ctgtggggac     60
ggctccgacg aggcctnctg ccccaaggtg aacgtcgtca cttgtaccaa acacacctac    120
cgctgcctca atgggctctg cttgagcaag ggcaaccctg agtgtgacgg gaaggaggac    180
tgtagcgacg gctcagatga gaaggactgc gactgtgggc tgcggtcatt cacgagacag    240
gctcgtgttg ttgggggcac ggatgccgga tgagggacga gtggccctgg caggtaagcc    300
tgcatgctct gggccagggc cacatctgcg gtgcttccct catctctccc aactggctgg    360
tctctgccgc acactgctac atcgatgaca gaggattcag gtactcagac cccacgcagt    420
gaacggcctt cctgggcttg cacgaccaga gccagcgcag cccccttggg gtgcaggagc    480
gcaggctcaa gcgcatcatc tcccacccct tcttcaatga cttcaccttc gactatgaca    540
tcgcgctgct ggagctggag aaaccggcag agtacagctc catggtgcgg cccatctgcc    600
tgccggacgc ctcccatgtc ttccctgccg gcaaggccat ctgggtcacg ggctggggac    660
acacccagta tggaggcact ggcgcgctga tcctgcaaaa gggtgagatc cgcgtcatca    720
accagaccac ctgcgagaac ctcctgccgc agcagactca cgccgcgcat gatgtgcgtg    780
ggcttcctca gcggcggcgt ggactcctgc cagggtgatt ccgggggacc cctgtccagc    840
gtggaggcgg atgggcggat cttccaggcc ggtgtggtga gctggggaga cggctgcgct    900
cagaggaaca agccaggcgt gtacacaagg ctccctctgt ttcgggactg gatcaaagag    960
aacactgggg tataggggcc ggggccaccc aaatgtgtac acctgcgggg ccacccatcg   1020
tccaccccag tgtgcacgcc tgcaggctgg agactggacc gctgactgca ccagcgcccc   1080
cagaacatac actgtgaact caatctccag ggctccaaat ctgcctagaa aacctctcgc   1140
ttcctcagcc tccaaagtgg agctgggagg tagaagggga ggacactggt ggttctactg   1200
acccaactgg gggcaaaggt ttgaagacac agcctccccc gccagcccca agctgggccg   1260
aggcgcgttt gtgcatatct gcctcccctg tctctaagga gcagcgggaa cggagcttcg   1320
gggcctcctc agtgaaggtg gtggggctgc cggatctggg ctgtgggccc ttgggccacg   1380
ctcttgagga agcccaggct cggaggaccc tggaaaacag acgggtctga gactgaaatt   1440
gttttaccag ctcccagggt ggacttcagt gtgtgtattt gtgtaaatga gtaaaacatt   1500
ttatttcttt ttaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aan          1553
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 11
<211> LENGTH: 2128
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  11
ccgcctgcga gcccgtgagc ttctacacgc agcccttctc gcactatggc caggccctgt     60
gcgtgtcctt cccgcagccc tgccgcgccg ccnacccccg cgtccgctgc tcacctaccg    120
cgtcggggag ggacccgggg tttgctggtt ggctcccgag cagacagcag gaaagaagaa    180
gcccttcgtg tacacccagg gccaggctgt cctaaaccgg gccttcttcc cttgcttcga    240
cacgcctgct gttaaataca agtattcagc tcttattgag gtcccagatg gcttcacagc    300
tgtgatgagt gctagcacct gggagaagag aggtccaaat aagttcttct tccagatgtg    360
tcagcccatc ccctcctatc tgatagcttt ggccatcgga gatctggttt cggctgaagt    420
tggacccagg agccgggtgt gggctgagcc ctgcctgatt gatgctgcca aggaggagta    480
caacggggtg atagaagaat ttttggcaac aggagagaag ctttttggac cttatgtttg    540
gggaaggtat gacttgctct tcatgccacc gtcctttcca tttggaggaa tggagaaccc    600
ttgtctgacc tttgtcaccc cctgcctgct agctggggac cgctccttgg cagatgtcat    660
catccatgag atctcccaca gttggtttgg gaacctggtc accaacgcca actggggtga    720
attctggctc aatgaaggtt tcaccatgta cgcccagagg aggatctcca ccatcctctt    780
tggcgctgcg tacacctgct tggaggctgc aacggggcgg gctctgctgc gtcaacacat    840
ggacatcact ggagaggaaa acccactcaa caagctccgg tggaagattg aaccaggcgt    900
tgacccggac gacacctata atgagacccc ctacgagaaa ggtttctgct ttgtctcata    960
cctggcccac ttggtgggtg atcaggatca gtttgacagt tttctcaagg cctatgtgca   1020
tgaattcaaa ttccgaagca tcttagccga tgactttctg gacttctact tggaatattt   1080
ccctgagctt aagaaaaaga gagtggatat cattccaggt tttgagtttg atcgatggct   1140
gaataccccc ggctggcccc cgtacctccc tgatctctcc cctggggact cactcatgaa   1200
gcctgctgaa gagctagccc aactgtgggc agccgaggag ctggacatga aggccattga   1260
agccgtggcc atctctccct ggaagaccta ccagctggtc tacttcctgg ataagatcct   1320
ccagaaatcc cctctccctc ctgggaatgt gaaaaaactt ggagacacat acccaagtat   1380
ctcaaatgcc cggaatgcag agctccggct gcgatggggc caaatcgtcc ttaagaacga   1440
ccaccaggaa gatttctgga aagtgaagga gttcctgcat aaccagggga agcagaagta   1500
tacacttccg ctgtaccacg caatgatggg tggcagtgag gtggcccaga ccctcgccaa   1560
ggagactttt gcatccaccg cctcccagct ccacagcaat gttgtcaact atgtccagca   1620
gatcgtggca cccaagggca gttagaggct cgtgtgcatg gcccctgcct cttcaggctc   1680
tccaggcttt cagaataatt gtttgttccc aaattcctgt tccctgatca acttcctgga   1740
gtttatatcc cctcaggata atctattctc tagcttaggt atctgtgact cttgggcctc   1800
tgctctggtg ggaacttact tctctatagc ccactgagcc ccgagacaga gaacctgccc   1860
acagctctcc ccgctacagg ctgcaggcac tgcagggcag cgggtattct cctccccacc   1920
taagtctctg ggaagaagtg gagaggactg atgctcttct tttttctctt tctgtccttt   1980
ttcttgctga ttttatgcaa agggctggca ttctgattgt tcttttttca ggtttaatcc   2040
ttattttaat aaagttttca agcaaaaatt aaaaaaaaaa aaaaaaaaga gcggccgctc   2100
gcgatntaga actagnggac gggggtcn                                      2128
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 12
<211> LENGTH: 594
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: thimet oligopeptidase
<400> SEQUENCE:  12
cccccgcgtc cgtaaatatt gaaaactcca ggcatcgaaa acaagagcag aagcaccttc     60
agccacagcc ttataaaagg gaaggtaaat ggcataaata tggtcgcact aatggaagac    120
aaatggcaaa tcttgaaata gaattggggc aattaccttt tgatcctcaa tactgattca    180
caattgagtt aaattagaca actgtaagag aaaaatttat gctttgtata atgtttggta    240
ttgaaactaa tgaaattacc aagatgacaa tgtcttttct tttgtttcta agtatcagtt    300
tgataacttt atattattcc tcagaagcat tagttaaaag tctactaacc tgcattttcc    360
tgtagtttag cttcgttgaa ttttttttga cactggaaat gttcaactgt agttttatta    420
aggaagccag gcatgcaaca gattttgtgc atgaaatgag acttcctttc agtgtaagag    480
cttaaagcaa gctcagtcat acatgacaaa gtgtaattaa cactgatgtt ttgtgttaaa    540
tttgcagcag agcttgagaa aagtcatttg gtctggaatt catcattaac attn          594
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 13
<211> LENGTH: 540
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: thimet oligopeptidase
<400> SEQUENCE:  13
aatacaatca tgcggcctgc ttcggtctcc agcctggctg ccttctgcct gatggaagcc     60
ggatgatggc agtggctgcc ctcgtggtga acttctcaca gccagtggca ggtcgtccct    120
ctctcctgag acacgacgag gtgaggactt actttcatga gtttggtcac gtgatgcatc    180
agatttgtgc acagactgat tttgcacgat ttagcggaac aaatgtggaa actgactttg    240
tagaggtgcc atcgcaaatg cttgaaaatt gggtgtggga cgtcgattcc ctccgaagat    300
tgtcaaaaca ttataaagat ggaagcccta tttgcagacg atctgcttga aaaacttgtt    360
gcttctaggc tgggtcaaca caggtcttct gaccctgcgc cagaattgtt ttgaagcaag    420
ttgatcagtc tcttcatacc aacacatcgc tggatgctgc aagtgaatat gccaaatact    480
gctcanaaat nttanggagt tgcagctact ccaggcacaa atatgccagc tacctttggn    540
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 14
<211> LENGTH: 466
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: thimet oligopeptidase
<400> SEQUENCE:  14
ttatcctgtc ttggtttcct tattgaatag atttccacag gaaaaatact gtgagtttac     60
tgatctgctg cagaattgga atttagactc acaataaaga gagttaaaga tagatccaaa    120
ggttcactta aaataaaaat caccagacag aacaggctac tgaagagtct cttccccgtg    180
gttaagtttc atcatacaca taaggctttg gagcagctgt cctcaaatgc ttctatccaa    240
aacccactcc tcttctggag tttctgaacc ctttatgttc cacatccacc tcctctctct    300
tcccatggct ctctacagag ccatttgtga catgtctacc tgacactttt ggggacgtgg    360
taagtaaaag aggcaaagtc cctaacactt attagaaacg tgagaagaga aaaatggtgc    420
ttgggacttg ctttagtatt ctaattgggc acacatgcca aaagac                   466
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 15
<211> LENGTH: 1477
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  15
cctcttttcc cccgatccaa ggatgtatgc atggaggtcg tatctatcca gtcttgggaa     60
cgtactggga caactgtaac cgttgcacct gccaggagaa caggcagtgg cagtgtgacc    120
aagaaccatg cctggtggat ccagacatga tcaaagccat caaccagggc aactatggct    180
ggcaggctgg gaaccacagc gccttctggg gcatgaccct ggatgagggc attcgctacc    240
gcctgggcac catccgccca tcttcctcgg tcatgaacat gcatgaaatt tatacagtgc    300
tgaacccagg ggaggtgctt cccacagcct tcgaggcctc tgagaagtgg cccaacctga    360
ttcatgagcc tcttgaccaa ggcaactgtg caggctcctg ggccttctcc acagcagctg    420
tggcatccga tcgtgtctca atccattctc tgggacacat gacgcctgtc ctgtcgcccc    480
agaacctgct gtcttgtgac acccaccagc agcagggctg ccgcggtggg cgtctcgatg    540
gtgcctggtg gttcctgcgt cgccgagggg tggtgtctga ccactgctac cccttctcgg    600
gccgtgaacg agacgaggct ggccctgcgc ccccctgtat gatgcacagc cgagccatgg    660
gtcggggcaa gcgccaggcc actgcccact gccccaacag ctatgttaat aacaatgaca    720
tctaccaggt cactcctgtc taccgcctcg gctccaacga caaggagatc atgaaggagc    780
tgatggagaa tggccctgtc caagccctca tggaggtgca tgaggacttc ttcctataca    840
agggaggcat ctacagccac acgccagtga gccttgggag gccagagaga taccgccggc    900
atgggaccca ctcagtcaag atcacaggat ggggagagga gacgctgcca gatggaagga    960
cgctcaaata ctggactgcg gccaactcct ggggcccagc ctggggcgag aggggccact   1020
tccgcatcgt gcgcggcgtc aatgagtgcg acatcgagag cttcgtgctg ggcgtctggg   1080
gccgcgtggg catggaggac atgggtcatc actgaggctg cgggcaccac gcggggtccg   1140
gcctgggatc caggctaagg gccggcggaa gaggccccaa tggggcggtg accccagcct   1200
cgcccgacag agcccggggc gcaggcgggc gccagggcgc taatcccggc gcgggttccg   1260
ctgacgcagc gccccgcctg ggagccgcgg gcaggcgaga ctggcggagc ccccagacct   1320
tccagtgggg acggggcaag ggcctggcct gggaagagca cagctgcaga tcccaggcct   1380
ntggcgcccc cactcaagac taccaaaagc caggacacct caagtcttca gccccactac   1440
cccaccccac tcctgtattc tttttttttt ttttaan                            1477
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 16
<211> LENGTH: 331
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  16
atttaaaaac agtgaaaaga aaaanaaata ncngangaat aagaatacag ggctgggngc     60
agnggctcag gcctgcaatc ccagcacttn gggaggcgga ggcaggngga ccgcttgagc    120
ccaggngttc gagaccagcc tgggcaacac agtgagaccc ccctctttac aaaaaataca    180
aaantnagcc aggngtggng gngcacctgt agncccagct acttgagagg ctgaggnggg    240
agggtcactt gancccaggn ntcggaggtt acagtgagcc ctganggnca ctgcactcca    300
acctggggca acggagcaag nccctgtcta a                                   331
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 17
<211> LENGTH: 474
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  17
gaattcggga acgatgggga gcaccaggca ggtggtcctc gctgtgacac tgaggtgctg     60
agccagtgag ctagggtgga ggggctgtgt ttattggaac aaagggtggt accaaaatgc    120
atccccatga cccacagccc ccccacaccc gtccttgggt agggtacggt ggggtggggt    180
gttgggtggc ctgctgctcc tgttgctttc acgtagagtc tcggcctggg cagtcacgtg    240
gtggtcactc ctggatgtgc tgtcctatcc agcctctcac agctgccacc cgggtataga    300
cacctgggaa gtggggccgg ccacagccat agccccagct agtgacccca gttagcaccc    360
accgtccaga gggctccctg caggccaggg gtcccccagc gtcaccctgt tggggagaga    420
agaaaggggg ttcagaggcc ggtacctccc ctacagcagc ccttgggtca ttgg          474
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 18
<211> LENGTH: 147
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  18
ttcctcttgg ttgcaaccng nggctgtaga ggccgnggtt tggggaagnc ggngcttggt     60
tcggcccaat ngttttggtt ccgggttaag ncaatctccc ggcntccaag ngcccncngt    120
tttccgccga ccccggttcn cttggtt                                        147
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 19
<211> LENGTH: 611
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trpsin-like serine proteases
<400> SEQUENCE:  19
tcgtccgtaa tttttttttt tttgtgatca aagatgttta tttaaatgca gattttacaa     60
cctcaacttg tccctttaca acaggtcttc ccagagcttt taatgtgcag acaggcatgt    120
gaacctctga taaagagagg gaaaatggag aggcatcttc ctctgactta atacaaccct    180
ttttactttt ggtagaaaat cataaggcat gagtgtttaa ggagcacact ttgggaaatg    240
tggttctact agccttacta ggcaaatatg ctcggaagcg tgataactaa cacatgtaaa    300
gcactaatta tattaataat gccatgagtc cttttttctt tttctgtcta cttctatgat    360
agtttaatac catgctttct tttattatca ctaaaaagat ggacatgttg aattatttta    420
taattttctt ttacagttct gtgagttaag ctgtatatag catatgggtg tatcattctt    480
tagtaaatta catctacttg tgaactaaac attgatttca ttttgacttt gtgccattgt    540
ctaactttgc aaaaaatcaa aatcaaggaa tcaaggggct tcncaaaang aacatctatt    600
tttttaaaaa n                                                         611
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 20
<211> LENGTH: 1364
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  20
tttttttttt ttttacattt ctcaactttt attgtgggcc cttcaaccat ttttgctgct     60
gggtttcata ttttcggatt gtttcacgga tccacaggac gtatcttgag acacgggtgt    120
agacaccagg ccggtcaggt tgcccacatg ggaagtctcc ccaggagacg atgccataca    180
gtgttctgtt acagaccagg gggcccccag agtcaccctc acaggagtct ttgccaccct    240
cttttgtgcc ggcacacaac atgttgtcag tgatctttcc tgggtagact tgacgacact    300
cctcatctga gcgaagttgg atgttggcac attgtagagt tttggggtaa ttcactcaga    360
ccttccctcc catctctgcc cctgtttccc cagccactcc tatggggcct caggcacctg    420
tgtgggtgca taccctgggg gctggtggtg gtgccccagc cagacacccg acaggtggtg    480
ccaggggtta ggcggttgtt gtgggaaagg ggcagggttt ggatgtagcc tgtgagctgg    540
accggggact gcagctccag aagcatgatg tcatggtngt ggttcaggtg ggtggggctt    600
ctccggtatt cagggtgggg gatagagtgg acaacttccc tcacctgctc accagcttcc    660
acacgcccta gggcgtgctt gcctaggtaa actttgagcc cctcctttag acagtgtgcg    720
gcagtgagga cccatttggg gtggaccagg acttccccca cagagtagcc gcccttgcac    780
tagtagggca gcctgccagg gctgagagtg ggggaagcag gtgtagccac ctgggagaaa    840
cccactggtc ccattggtgt tgagaacctt ggaagactcc tgggagacac ctgagtgagg    900
ggcccacgag gagcgtcacg gaggtccagg gggcagagga gccctggggt tgtggtttct    960
gggtttgggg taagggtcgg attattgccc tgggtgacca ggaactgaag atgaatttgc   1020
cgacctatgg cagttgctat tcttgaccaa gtggagatga attagggcaa aggggtgaca   1080
ttattttctc aggaagtacc aaatcctcca ctgggggtta acagaagagt tcacaaaatg   1140
aggatgttgc tgataggtaa gcaggagcct gactttctct ccacatgcat tttttatatc   1200
attctaccag aagatggatt tcaggaggta gaagtgagac tgacctacac atccacctag   1260
gcaatatcta tccatcaatc tatccaatca tccatccccc attcatccta ttgatttgtc   1320
catccgtcta ctcatccatc tatccattca tccatttagg tagn                    1364
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 21
<211> LENGTH: 416
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  21
tttttttttt tttggtcgtc ttggtgtatt ttatttctat ttgcaactgt actatagggc     60
tggccatata gtatttgata agtgaacaaa tgagtgaatg gatgaatgat gagtgaatga    120
atgaatgaat gaatgaatga agtcttcttt gacgtcccct gtccacagtg atcttctgag    180
aacctctgca gcatttcctt tgtgtagcct cctttggtcc ttagcaacaa cgttgtagca    240
attagttgtt tgaatgtgta ctcagcttaa gttctcgact gcagggtaag caatttgcca    300
gtctagagcc aggtggggag acattgcttg ggaatcagat cgacctggtt ccaatcccag    360
agctaccacc tattacttgt ggcctcaggt aattatctct ctgtaaagct ccattt        416
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 22
<211> LENGTH: 610
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  22
aatgcccttc ccagcggtat atctccctcc agtgttccca ctgcggactg agggccatga     60
ccgggcggat cgtgggaggg gcgctggcct cggatagcaa gtggccttgg caagtgagcc    120
tgcacttcgg caccacccac atctgtggag gcacgctcat tgacgcccag tgggtgctaa    180
ttgcggccca ctgcttcttc gtgacccggg agaaggtcct ggagggctgg aaggtgtacg    240
cgggcaccca gnaacctgca cccagttgcc tgaggcagcc tccattgccg agatcatcat    300
caacagcaat tacaccgatg aggaggacga ctatgacatc gccctcatgc ggctgttcaa    360
gccccttgac cctgttccgg tgagggaatc tgcactcccc gctctcctgc cccccagccc    420
cagcaccctc tgcagccctc gcacttgtca gcatctgtca actcatatcc gggccccaaa    480
gcttctgcag ggcagaagtc aaagactctt aaagatcctt acatggaaca cttctgtttt    540
ataattaggg aaactgaagc ccaagggtta taaataagtt tgctccaaat gacacatctc    600
acattacaaa                                                           610
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 23
<211> LENGTH: 481
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  23
gcgtccggtt tttaactcct gcctcccaca tgttcttgac tgataactga ctcatgtccc     60
tgaattaaaa tgactgacct atgacagcat caagcattct ttgtaagcag agtgatatat    120
ctgagagggc gttgacctgt tgtgtagaat acatatcctt tcccccttca gaatcctgtc    180
tcgcctcgta actgggagag aggctgtgcc tgaaactagg ggcgatgtca aggaagctag    240
aggcctcgat gcaattatta ctgactctgg ggaggaagac agagaataag gggacaccaa    300
ctgcccagtc cactggccat ttttaagggt ccccccaccc caagccaaag tttggtttgt    360
tgctgttaag acaatttttg ttgtatgtat ataaatattt tanttagagg agccggggaa    420
tgggatgccg gctttcacag ttctanggaa tgggggcagg gagggatttt gctttttgct    480
t                                                                    481
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 24
<211> LENGTH: 2234
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  24
cccgcgtccg ggcggggcgg gcgggcctcg ggtggcgcgg ggggcggacc cgccagctgc     60
ctgcgctgct cgccagcttg ctcgcactcg gctgtgcggc ggggcaggca tgggagccgc    120
gcgctctctc ccggcgccca cacctgtctg agcggcgcag cgaagccgcg gcccgggcgg    180
gctgctcggc gcggaaacaa tgctcggcat ggcatgggat tcctgggctc ctcttccttc    240
tcttctttct gctctgtgct gttgggcaaa gtgagccctt acagtgcccc ctggaaaccc    300
acttggcctg cataccgcct ccctgtcgtc ttgccccagt ctaccctcaa tttagccaag    360
ccagactttg gagcccgaaa gccaaattag aaagtatctt cttcatgtgg accccagtgt    420
cataagggaa ctccactgcc cacttacgaa gaggccaagc aatatctgtc ttatgaaacg    480
ctctatgcca atggcagccg cacagagacg ccaggtgggg catctacatc ctcagcaagt    540
agtggagatg gggcccaaca ccgagatcaa gggtcttagg gaaagtctcg aaggaagcgg    600
cagatttatg gctatgacag gcaggttcaa gcatttttgg ggaaggactt cctgctcaac    660
taccctttct caacatcagt tgaaatttat ccacgggctt gcaccggcac cctggtggca    720
gagaagcatg tcctcacagc tgcccactgc atacacggat ggaaaaaccc tatgtgaaag    780
ggacccagaa gctttcgagt gggcttccta aagcccaagt ttaaagatgg gtggtcgagg    840
ggccaacgac tccacttcag ccatgcccga gcagatgaaa tttcagtggg atccgggtga    900
aacgcaccca tgtgcccaag ggtttggatc aagggcaatg ccaatgacat cggcatggat    960
tatgattatg ccctcctgga actcaaaaag cccccacaag agaaaattta tgaaagattt   1020
ggggtgaccc tccctgcata agccagcttg ccaagggggc aagaattcca cttctctggt   1080
tatgacaaat gaccgaccca ggcaatttgg tgtatcgctt ctgtgacgtc aaagacgaga   1140
cctatgactt gctctaccaa gcaatgcgat gcccaaccag gggccagcgg gtcttggggt   1200
ctatgtgagg gatgtggaaa gagacagcag cagaagttgg gaccgaaaaa ttattggcat   1260
tttttcaggg caccagtggg tggacatgaa tggttcccca caggatttca acgtggctgt   1320
cagaatcact cctctcaaat atgcccagat ttgctattgg attaaaggaa actacctgga   1380
ttgtagggag gggtgacaca agtgttccct cctggcagca attaaggggt cttcatgttc   1440
ttattttagg agaggccaaa ttgttttttg tcattggcgt gcacacgtgt gtgtgtgtgt   1500
gtgtgtgtgt gnaangtgnc ntataatctt ttacctattt cttacaattg caagatgact   1560
ggctttacta tttgaaaact gctttgtgta tcatatcata tatcatttaa gcngttngaa   1620
cgcatacttt tgcatagaaa tananaaaat ctgatttggg gcaatgagga atatttgaca   1680
attaagttaa tcttcacagt ttttgcaaac tttgattttt atttcatctg aacttgtttc   1740
aaagatttat attaaatatt tggcatacaa gagatatgaa ttcttatatg tgtgcatgtg   1800
tgttttcttc tgagattcat cttggtggtg ggttnttttg tttttttaat tcagtgcctg   1860
atctttaatg cttccataag gcagtgttcc catttaggaa ctttgacagc atttgttagg   1920
cagaatattt tggatttgga ggcatttgca tggtagtctt tgaacagtaa aatgatgtgt   1980
tgactatact gatacacata ttaaactata ccttatagta aaccagtatc ccaagctgct   2040
tttagttcca aaaatagttt cttttccaaa ggttgttgct ctactttgta ggaagtcttt   2100
gcatatggcc ctcccaactt taaagtcata ccagagtggc caagagtgtt tatcccaacc   2160
cttccattta acaggatttc actcacattt ctggaactag ctatttttca gaagacaata   2220
atcagggctt aatt                                                     2234
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 25
<211> LENGTH: 373
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  25
tcgctcggtg aggacgttcc cggacagtgc ctcactcacc tgggcactgg tatcccctcc     60
cagggtccac caagggctcc tgcttttcag acaccccatc atcctcgcgc gtcctcaccc    120
tgtctctacc aggggaagtt gcctagcttg gtgaggttac tcctgctcct ccaacctttt    180
tttgccaagg tttgtacacg actcccatct aggctgaaaa cctagcaagt ggaccttgtg    240
tgtgtgcatg gtgtcagccc aaagccaggc tgagacagtc ctcatatcct cttgagccaa    300
actgtttggg tctcgttgct ttatggtatg gtctggattt gtgggaatgg ctttgcgtga    360
gaaaggggag gag                                                       373
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 26
<211> LENGTH: 1619
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  26
ccgcgtccgg aaatatgaag aactgaggag gaaaaaaaaa aaaaaagaaa agaaccaaca     60
acctcaactg cctactccaa aatgttggtc attttatgtt aagggaagaa ttccagggtt    120
atggccatgg agtgtacaag tatgtgggca gattttcagc aaactctttt cccactgttt    180
aaggagttag tggattactg ccattcactt cataatccag taggatccag tgatccttac    240
aagttatgaa aacataatct tctgccttct catgatccaa ctaatgcctt actcttcttg    300
aaattttaac ctatgatatt ttctgtgcct gaatatttgt tatgtaaata acaagacctc    360
agtgccttcc tgtttttcac attttccttt tcaaataggg tctaactcag caactcgctt    420
taggtcagca gcctccctga agaccaaaat tagaatatcc atgacctagt tttccatgcg    480
tgtttctgac tctgagctac agagtctggt gaagctcact tctgggcttc atcttggcaa    540
catctttatc ccgtaatggg tatggttgac actagcccaa tgaaatgaat taaagtggac    600
caatagggct gagctctctg tgggctggca gtcctggaag ccagctttcc ctgcctctca    660
tcaactgaat gaggtcagca tgtctattca gcttcgttta ttttcaagaa taatcacgct    720
ttcctgaatc caaactaatc catcaccagg gtggtttagt ggctcaacat tgtgttccca    780
tttcagctga tcagtgggcc tccaaggagg ggctgtaaaa tggaggccat tgtgtgagcc    840
tatcagagtt gctgcaaacc tgacccctgc tcagtaaagc acttgcaacc gtctgttatg    900
ctgtgacaca tggcccctcc ccctgccagg agctttggac ctaatccaag catccctttg    960
cccagaaaga agatggggga ggaggcagta ataaaaagat tgaagtattt tgctggaata   1020
agttcaaatt cttctgaact caaactgagg aatttcacct gtaaacctga gtcgtacaga   1080
aagctgcctg gtatatccaa aagcttttta ttcctcctgc tcatattgtg attctgcctt   1140
tggggacttt tcttaaacct tcagttatga tttttttttc atacacttat tggaactctg   1200
cttgattttt gcctcttcca gtcttcctga cactttaatt accaacctgt tacctacttt   1260
gactttttgc atttaaaaca gacagtggcg tggatatagt tttactttta aactgtgtac   1320
ataactgaaa atgtgctata ctgcatactt tttaaatgta aagatatttt tatctttata   1380
tgaagaaaat cacttaggaa atggctttgt gattcaatct gtaaactgtg tattccaaaa   1440
catgtctgtt ctacatagat gcttagtccc tcatgcaaat caattactgg tccaaaagat   1500
tgctgaaatt ttatatgctt actgatatat tttacaattt tttatcatgc atgtcctgta   1560
aaggttacaa gcctgcacaa taaaaatgtt taaccggtta aaaaaaaaaa aaaaaaagg    1619
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 27
<211> LENGTH: 216
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  27
cgatgcctgt tctncaaaag cagtggtttc tttacgctgt ntagcctgcg gggtcaactt     60
gaactcaagc cgccagagna ggatcgtggg cggcgagagc gcgctcccgg gggcctggcc    120
ctggnaggtc agcctgcacg cccagaacgt ccacgtgtgc ggaggntcca tcatcacccc    180
cgagtggatc gtgacagccg cccactgcgt ggaaaa                              216
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 28
<211> LENGTH: 340
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  28
ctggggtctg atcacagggt caccaggatg cccaggggca tcaccagaca caggactagg     60
atgaggaagt ctttgaattc aaacaggaag cttgtctcag gtgatcaata atccatttct    120
tgtagaaact aacttctgtg taaactccag ggtatccttt gcgaccgcag ccaatgcccc    180
agctcacaat ccccacctgg acccatgtgc catttaattc acagaccagg ggccccccag    240
aatctccctg gaaaaagaaa gacagtcact gtaggaaaga aataggatcc acatcagagc    300
aggctaattg cactgcaatg cgctacagag ctaagcacta                          340
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 29
<211> LENGTH: 340
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  29
ctggggtctg atcacagggt caccaggatg cccaggggca tcaccagaca caggactagg     60
atgaggaagt ctttgaattc aaacaggaag cttgtctcag gtgatcaata atccatttct    120
tgtagaaact aacttctgtg taaactccag ggtatccttt gcgaccgcag ccaatgcccc    180
agctcacaat ccccacctgg acccatgtgc catttaattc acagaccagg ggccccccag    240
aatctccctg gaaaaagaaa gacagtcact gtaggaaaga aataggatcc acatcagagc    300
aggctaattg cactgcaatg cgctacagag ctaagcacta                          340
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 30
<211> LENGTH: 511
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  30
catcacagtc atccacgggc actgttatgg gagctgttat catggagggc ttctacgttg     60
tctttgatcg ggcccgaaaa cgaattggct ttgctgtcag cgcttgccat gtgcacgatg    120
agttcaggac ggcagcggtg gaaggccctt ttgtcacctt ggacatggaa gactgtggct    180
acaacattcc acagacagat tagtcaaccc tcatgaccat agcctatgtc atggctgcca    240
tctgcgccct cttcatgctg ccactctgcc tcatggtgtg gtcagtggcg ctgcctccgc    300
tgcctgcgcc agcagcatgg aatgactttg ctgatgacat ctccctgctt gaagtgaagg    360
aggcccatgg gaagaaagat agagattccc ctggaccaca ccttccgtgg ttcactttgg    420
tcacaagtag gagacacaga tggcacctgt ggccagagca cctcaggacc cttcccacca    480
ccaaatgcct ctgccttgat ggagaaggaa a                                   511
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 31
<211> LENGTH: 434
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  31
aattcaagag gcaatctttg caccaatgtt aggcttgttt atacagtccc tgtctctaaa     60
gcaaatagca aactgtgcat cctctcctac tgactttggc cagcagggaa acaagcttgg    120
tctcttctct gccagggtac cacagggaca cacgccaagg taacctgcgt gtgatgccag    180
tacttctgaa actaagaaaa gaagaatact ttgggttgga gaatttaaag gaatggtgga    240
caaaggttca gggctgaaag tttcaagcag cagaatttcc cgacttaaat ttgaggtgac    300
caagagtaat tcccgccagc aggagttgct tcttttcttc tcttttttct ggttttccta    360
acanggtaca agttccctgg gaaccccacc ctttggccaa gcctttttcc cttcttccat    420
ccaagggcna gagg                                                      434
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 32
<211> LENGTH: 2514
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  32
acaagttgca cttaagaagc tatgctaaga aaacaaacac acagaagcct acatcattac     60
atgtatagaa tgttcaagaa ctgatgaaac cagtccgtgg tcacaaaagc cagaaagtgg    120
ttgcttctgg ggaccagaag ggaaaggggc ataaaggaac cttttgaggt gaatagaagt    180
ttctgcatct tggtttggca cacatgccaa aactcaccag ctacagattc tcgttgacac    240
tggaagcagt aactttgccg tggaggaacc ccgcactcct acatagacac gtactttgac    300
acagagaggt ctagcacata ccgctccaag ggctttgacg tcacagtgaa gtacacacaa    360
ggaagctgga cgggcttcgt tggggaagac ctcgtcacca tccccaaagg cttcaaatac    420
ttcttttctt gtcaacattg ccactatttt tgaatcagag gaatttcttt ttgcctggga    480
ttaaatggaa tggaatactt ggcctagctt atgccacact tgccaagcca tcaagttctc    540
tggagacctt cttcgactcc ctggtgaaca caagcaaaac atccccaaac gttttctcca    600
tgcagatgtg tggagccggg cttgcccgtt ggctgggatt ctggggaacc aacggaggta    660
gtcttgtctt gggtggaatt gaaccaagtt tgtataaagg agacatctgg tataccccta    720
ttaaggaaga gtggtactac cagatagaaa ttcttgaaat tgggaaattg ggaggccaaa    780
gctttaattc ttgggactgc aggaggagta ttaacgcaga caagggccat cgttggacag    840
tgggcaccac gctgctgcgc cttgccccca gaaggtgttt gatgcggtgg tgggaagctg    900
tggcccgcgc atctctgatt ccagaattct ctgatggttt ctggactggg tcccagctgg    960
cgtgctggac gaattcggaa acaccttggt cttacttccc taaaatctcc atctacctga   1020
gagacgagaa ctccagcagg tcattccgta tcacaatcct gcctcagctt tacattcagc   1080
ccatgatggg ggccggcctg aattatgaat gttaccgatt cggcatttcc ccatccacaa   1140
atgcgctggt gatcggtgcc acggtgatgg agggcttcta cgtcatcttc gacagagccc   1200
agaagagggt gggcttcgca gcgagcccct gtgcagaaat tgcacggtgc tgcaagtgtc   1260
tgaaatttcc gggcctttct caaacagagg atgtagccag ccaactgtgt ccccgctcaa   1320
gtctttgagc gacgcccatt ttgtggattg tgtccctatg ccgctcaatg aagcgtctgt   1380
ggaagccatc ctccttgtcg ttaattcagt cgctgctgct gcttgccgtt ccggtgtcag   1440
cgtcgccccc gtgaccctga ggtcgtcaat gatgagtcct ctctgggtca gacatcgctg   1500
gaaatgaata gccaggcctg acctcaagca accatgaact cagctattaa gaaaatcaca   1560
tttccagggc agcagccggg atcgatggtg gcgctttctc ctgtgcccac ccgtcttcaa   1620
tctctgttct gctcccagat gccttctaga ttcactgtct tttgattctt gattttcaag   1680
cttttcaaat cctccctact tccaagaaaa ataattaaaa aaaaaacttc attctaaacc   1740
aaaacagagt ggattgggct gcaggctcta tggggttcgt tatgccaaag tgtctacatg   1800
tgccaccaac ataaaacaaa accaagcctt ggctcgttct cttctctctt caatctctgg   1860
aaaaataagt acatatagtt gataacccct cttagcttac aggaagcttt ttgtattaat   1920
tgcctttgag gttattttcc gccagacctt caacctgggt caaaagtggt acaggaaggc   1980
ttgcagtatg atggcaggag aatcagcctg gggcctgggg atgtaaccaa gctgtaccct   2040
tgagacctgg aaccagagcc acaggcccct tttgtgggtt tctctgtgct ctgaatggga   2100
gccagaattc aactaggagg tccatcaaac cgatggtcct cacaagcctc ttctgaagat   2160
gggaaggcct tttgcccgtt gaggtagagg ggaaggaaat ctcctctttt gtacccaata   2220
cttatgttgt attgttggtg cgaaagtaaa aacactacct cttttgagac tttgcccagg   2280
gtcctgtgcc tggatggggg tgcaggcagc ctttgaccac cgctgttccc ctcacccaaa   2340
agaattatca tcccaacagc caagacccaa caggtgctga actgtgcatc aaccaggaag   2400
agttctatcc ccaagctggc cactatcaca tatgcttact cttgcttaaa attaataaat   2460
catgttttga tgagaaaaaa ctaaaaaaac ccacgcgtcc gcggacgcgg ggcg         2514
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 33
<211> LENGTH: 265
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  33
cttcctantg cagttaaagg gccattgcca gtcagctgaa gaaggaaatg tttgcttctc     60
cctttaaggt gttaaagtaa tgcacagaaa ataaaaatag cagcctcata aatctgcacg    120
gcattgcatt caagcaaagg acaatatgag taacttngag anatatccac attcnatgca    180
cttaatgaaa tcctgttttc nttggagtta catgaggcag cagtactagc tagtgtctaa    240
tattgcactt ttatagcata aacac                                          265
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 34
<211> LENGTH: 393
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  34
ccacgcgtcc gcgccggccg agtcgctgag ccgcggctgc cggacgggac gggaccggct     60
aggctgggcg cgccccccgg gccccgccgt gggcatgggc gcactggccc gggcgctgct    120
gctgcctctg ctggcccagt ggctcctgcg cgccgccccg gagctggccc ccgcgccctt    180
cacgctgccc ctccgggtgg ccgcggccac naaccgcgta gttgcgccca ccccgggacc    240
cgggacccct gccgagcgcc acgccgacgg cttggcgctc gccctggagc ctgccctggc    300
gtcccccgcg ggcgccgcaa cttcttggcc atggtagaca acctgcaggg ggactctggc    360
cgcggctact acctggagat gctgatcggg acc                                 393
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 35
<211> LENGTH: 727
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  35
ttcagcctcc gctggatgcg attggtggag caagggctgc tggagaaacc cgtcttctcc     60
ttttacctca acagggattc tgaagggtct gatgggggag agctggtcct agggggctca    120
gaccccgcct cactacgtac ctcccctcac cttcatacca gtcaccatcc ctgccctact    180
ggagggtcca catggagaag tgtgaaaggt cgggcacaag ggcttaagcc tctgtgccca    240
agggctgcag tgccatccta gacacaggca catccctcat cacaggacct agtgaggaga    300
tccgggcctt gaataaagcc attgggggat atcccttcct gaatcgggca gtacttcatt    360
cagtgttcca agacgccaac gcttccccct gtctccttcc accttggtga agtctggttt    420
aacctcacag gccaggacta tgtcatcaag attcttcaga gcgatgttgg cctctgcctg    480
ttgggcttcc aagctttgga tatccccaaa gcctgcggga cccctcttgg aatccttggg    540
gacgtctttt tggggcccta tgtggctgtc tttgaccgtg gggacaaaaa cgtcgggccc    600
gcgcgtggga ctggcgcgtg ctcagtctcg ttcaacagac cgggcagaaa gaaggactac    660
gcaggcgcag ttcttcaaaa gacgccctgg ttagggtaca agctcaccgg gccacagcag    720
ctatgct                                                              727
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 36
<211> LENGTH: 693
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  36
agggaccctg aagagcctga tggaggagag ctggtcctgg ggggctcgga cccggcacac     60
tacatcccac ccctcacctt cgtgccagtc acggtccctg cctactggca gatccacatg    120
gagcgtgtga aggtgggccc agggctgact ctctgtgccc agggctgtgc tgccatcctg    180
gatacaggca cacctgtcat cgtaggaccc cactgaggaa atccgggccc tgcatgcagc    240
cattggggga atcgccgtgc tgactgggga gtacatcatc ctgtgctcgg aaaatcccaa    300
aagctccccc gcaagtctcc ctttccttct tgggggggtc tggtttaaac ttcacggccc    360
atgattacgt catccagatt acttcgaaat ggcgtccgcc tctgcttgtc cggtttccag    420
gccctggatg tccctccgcc tgcagggccc ttctggatcc tcggtgacgt cttcttgggg    480
gcctatgtga acctcttcga ccgcggggac attaaagacc ggcgcacgag tgggactggc    540
gcgcgctcgc cctccggagc ggacctggga agcgcgagac cggcaggcgc agttccccgg    600
gtgccgccca ggttgatgca tgcgcagcgg gtggtcgcgg aggtcctgct acccagtaaa    660
aatccactat ttccattgaa aaaaaaaaaa aaa                                 693
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 37
<211> LENGTH: 69
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  37
ggaattgtng taccncgcca gaacacangg gtcanngaaa acnaccccta aaagccanaa     60
tgggaaagg                                                             69
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 38
<211> LENGTH: 91
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  38
gatttagtac agagctcttt tttgaaatga aggctggaga tgtgcatttt tcacggtgtt     60
aactggttgt acttataaca agaaatgggg t                                    91
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 39
<211> LENGTH: 485
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  39
ctcataaaaa atgctgtaat cctgcagatt gtactctagt tagatctgca gaatgtggca     60
ctggatcatg ctgtaacaat aaaacttgta cgatccacga aagaggccat gtctgcagaa    120
aaagtgtaga tatgtgtgat tttccagaat attgcaatgg aacatctgag ttttgtgtac    180
ctgatgtgaa agctgctgat ttagaatact gcagtaataa gactagctat tgctttaaag    240
gagtatgcag agaaagggat agacagtgtt cacagttatt tggaaaattt gctaagtctg    300
ctaatcttct gtgtacagaa gaagtgaatt ttcaaaatga caaatttgga aactgtggtt    360
cccgttgtga tttttttgat atcctttgtg gaaagattgt ttgtcactgg atacattcag    420
aactagtacc aatgacagac ttagacatac aatatactta ccttagaggt cacgtatngt    480
tgtcg                                                                485
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 40
<211> LENGTH: 2350
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  40
cctctagact acttgtcgtc gtcgtccttg tagtcggaaa cagggggctg gttaggaggt     60
ccaagtgttg gctgtatccc cagaaactct aggctgttgt cattcagacg gaaagcatca    120
ttgatacggc tccgggacat cctgatggcc ttttcaactt cagttctagg aatgatatca    180
gacacatttt taggggcagt gaccaaagaa attaaaggag attcttggtt tcaaattagc    240
cactcgcaca tccttcctcc ccaaaaagaa tcatgctgat tttttacttt taaaaagtac    300
tgcctcatag catatgcaac agatgatcgg aacaggtaca tttcattgtc gttccattca    360
tatgctttat ctccaagagc tgattttagg ctttatcctc actttgatgc ttttggtctg    420
catatggact ccagtcggta ctccatccca caaaagaatt cttgttctgg tctttcagcc    480
aggtaaataa cgggctcaaa gtacgttgag cagtggcctt acattcatgt tcctttgctc    540
ctacaacatt ttccaatgct agggtccagg gttctgattt tccaagcctc agcatattga    600
acagtttctg tccagcttct gtagagttac gagatgtcac atttgtgcag agggccttca    660
tgtttagctg gttggacaaa gtgcttcttg aaactgggaa ttgggtaaag ggtccttgtg    720
taatatcgaa tgaatggagt aatcattaga aacatggaac agagatgcgg ggtcacagta    780
tgtttcatca tgggggcaca aggttcccaa ccaccccaac tatctctcgc ttcatctccc    840
accactttgt tcatccactg gtctttggga atttcccctt taaagaccat ccacctccac    900
ttctctaaca tgtaagtaaa tggcaggagt cccaacaatc gtgagtgctt tgtttgagca    960
ggaagtttat ttctgtttca ttgtcttctt gaaaattcgg gtgacaaaaa aaccaatggg   1020
attttaaatg cttaaggtgt ggctgcagaa agtgacatga tttccccaac agcttcatgg   1080
aatccttcat tagctccatt tcttaccaga aaaggttgtg cagcatatgc catatcatac   1140
tggatatgcc ccatctcatg atgagctgtc aggaagtcgt ccattgtcac ctttgtgcac   1200
attaaggatc ctgaaagtcg cccttccccc aggtcccaag ctgtgggatg gcagactgct   1260
ttctgaacat ttcctgggtc ccgttagcat ggaattttcc ccagaatcct tgagtcatat   1320
taggaagacc aacagataca aagaacttct cgggcctcct tgaatattct ctggtgcatc   1380
ccaggcctgg tccaccattg gcatcagtaa catcgtatgt ttggtttcct gtccaaaggg   1440
acactgtcaa agagtacaga tttgtcccaa aatctaaccc cacatatcac caagcgaaat   1500
gagcagggag gcatccaatt ggactgatat aggaaggata ggcattcatc aactttgccc   1560
tcacataggc atgaagatgt tcatataatg gtttaatctc ttcaaaaggt atgttccaca   1620
tcttcaatca actggccgcg gcatgtagtc atagccatct taccccattt actttcatag   1680
tctcctctcc aataatcccc atagtcctca taatgatttg ctcttgccat ctcatttttc   1740
aagaccacat actcttcata taatggcctc agctgcttgc cgacctcaga tctccagctt   1800
tcccaagccc agagcctctc attgtagtct aaactgtttg ccattatttc attcaaacct   1860
ggttcaagta ataagcattc ttgtggatta tctgggttac aaactttttc cagtactgta   1920
tgatggtgct cattgtattt agaattgtgt tcaaccgttt gctcttgtct tctgagagca   1980
ctgaagaccc attttgttga agagcctgca gatgaagctt gactgtgaga ttctgaattt   2040
cttgtagtgg atacatttgg gcaagtgtgg actgttcctt taaaaaggca cgaccatttt   2100
gtccccagca ttattcatgt tttggacatt ctcttcagta atattgggtg ttataattcc   2160
aagaagcaag tgaactttga tagaacaggt cttcggcttt cgtggttaaa cttgtccaaa   2220
aaatgtcttg gcctgttcct caatggtgga ctgagcagca gtctacagca acaaggctga   2280
gaaggagcca ggaagagctt gacatcgtcc cctgtgagcc aagatacctg ccccgggcgg   2340
cccgctcgag                                                          2350
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 41
<211> LENGTH: 387
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  41
actgcagtac cggtncggnt tcccgggtcg acccacgngt ccggcccgct tctcccagan     60
agtgtccgnc gtgtgcctgn ccagcgccga cgacgacttc cccgcgggga cactgtgtgc    120
caccacaggc tggggcaaga ccaagtacaa cgggtgactc tggaggcccc ctggtctgcc    180
agaaggacgg agcctggacc ctggtgggca ttgtgtcctg gggcagccgc acctgctcta    240
ccaccacgcc cgctgtgtac gcccgtntca ccaagctcat accctgggtg cagaagatcc    300
tggccgccaa ctgagcccgc agctcctgcc acccctgcct taagatttcc cattaaatgc    360
atctgtttag aaaaaaaaaa aaaaaaa                                        387
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 42
<211> LENGTH: 637
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  42
gccccgcgtc cgtccacctc aggttttaca ggtgctccca ccccagttga cggctcccac     60
ccacagggct gtctgtcaca aacccacctc tgttgggagc tattgagcca cctgggatga    120
gatgacacaa ggcactccta ccactgagcg cctttgccag gtccagcctg ggctcaggtt    180
ccaagactca gctgcctaat cccagggttg agccttgtgc tcgtggcgga ccccaaacca    240
ctgccctcct gggtaccagc cctcagtgtg gaggctgagc tggtgcctgg ccccagtctt    300
atctgtgcct ttactgcttt gcgcatctca gatgctaact tggttctttt tccagaagcc    360
tttgtattgg ttaaaaatta ttttccattg cagaagcagc tggactatgc aaaaagtatt    420
tctctgtcag ttccccactc tataccaagg atattattaa aactagaaat gactgcattg    480
aaggggagtt gtgggaaata agaagaatga aaagcctttt ttctgtccgc agatcctgac    540
ttttccaaag tgccttaaaa gaaataaaca aatgccctga gtggnaacta tgggtattta    600
ctttaaaacc aacttacctt tctggttttt ttttttt                             637
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 43
<211> LENGTH: 505
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  43
tttttttttt tctaaacaga tgcatttaat gggaaatctt aaggcagggg tggcaggagc     60
tgcgggctca gttggcggcc aggatcttct gcacccaggg tatgagcttg gcgacacggg    120
cgtacacagc gggcgtggtg gtagagcagg tgcggctgcc ccaggacaca atgcccacca    180
gggtccaggc tccgtccttc tggcagacca gggggcctcc agagtcaccc atgcaggagg    240
agacgccact ggccccggca cagatcatca cgtcggtgat ccccctgccc caggacttct    300
tgcattcggc attggacagg aggggcaagg ctgcctgctg cagcttggtc aggggtcttg    360
ttggcgttgt acttggtctt gccccagccc tgtgtgggac aaagtgttcc ccgcgggaaa    420
agtcgtcgtt ggcgactggg aaggcacacg ggggacactg tcctgggaaa accggtcagg    480
tgttggccag cttcaacagg gtgat                                          505
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 44
<211> LENGTH: 522
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  44
gaccacgcgt ccgccacncc cgncctnctg cngagacncn anaaggaatn cntgntcgct     60
nctnatgatg gatncnaaan tntcnanagt ttgacgaagt ggggctcggc ttccctgtaa    120
ccctctactc ctntagttcn tggtactgat anacaaaccc antctggatt ctgangaggg    180
cttaaaaaac ataggctata taaacatatn gttggagata tggttnacag ganaatccga    240
tgncaggntg tgcgaattag aaaatcccat naancctgac canattccct aatctntgtc    300
tgaaatctcc atagtnatcn ctgcacaagn tnttgnactc ctctgagact agnnatcngg    360
agctgatcca acacatttta ccctgacctn cttgaacctc gggccctaaa ctactggnat    420
cccgggttta atagnaaaac nccccggtcc cctanggtnc catntagggc cttctttaaa    480
aagngnnnnn aaatttgggt tnntttattt tttncccccc cc                       522
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 45
<211> LENGTH: 351
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  45
ccacgcgtcc ccggacgcgt gggcggacgc gtgggctgag ccagtgcgag actgaacttg     60
tgcagcctta gccaagacaa agcagtgttt ttcagcagac ggctgatggg acaggaattg    120
aagaagagaa ttgactcgta tgaacaggac agggtgaaaa tgctgggaat tataatggga    180
aacaaaacta tctatgttca tattttgtaa tatttcattt gttaagttta tatctggata    240
taatgttctt tttaaacaag tataatcata tcgtcggagg ttaagattat gaaattttaa    300
aatctctatt caagatgatg ttcactccaa atacactaca gaaatttagt c             351
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 46
<211> LENGTH: 554
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  46
gtccgccgac gcgtgggcgg acgcgtgggt ttttttcatt tccactgacc aataaacaga     60
actacaggtg cacccaacca cggacatgca ttaactcgtc atgagaaatc taggtaggct    120
aagtaggatg agagaatgtt tgtcactccc aaaaaatatc tggagaggaa gaatggagga    180
ttggcattga gatccatgtg gacaagctaa gtgggctctg tctgaaagct ggcattcatc    240
cacaacatta aaaaaatatc aaaataagaa aggctgtaaa ttaaaaagaa aacacagaaa    300
atactgctct cataaagatc tgattgcctt ggcacaggcc ctgtgggcag aatcaaacgc    360
atcactccca actcccattg cagaagaaaa gctattcaac tctcagcggt ggaggagtgc    420
atgtggcggg cagtttcagg tacaaaccga tgtactgcac tttcagacgc ggatcttgga    480
aatccaggac tttcttggtn aagttgactg aaggtatatt aggatatttc cccacaaaaa    540
tactatttgg gatt                                                      554
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 47
<211> LENGTH: 508
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  47
gacccgcgtc cgcggacgcg tgggcggacg cgtgggggaa cccaacacca gagctttgct     60
aataattagt gtggtcaaga gccgtctgag cctaatgagt cccagctgca ttaggttaag    120
agactcttcc agagccagcg ccaggtcttg aatggcacct ctccctagga tacacagcct    180
gcaggtcccc aggacctgga tgacacccgc ctcactgtgg cagtgtattg cctgttaatt    240
gctgctaatt ctaattctga tgatgactcc tactccattg tttaccccaa agcatcagct    300
aggctggagt gatttgttac aaatgagcaa aagatgagtc cttgcttccc tcagaaataa    360
aaggagctca gctgcagccg ttgcattggg cttcttggcc tcccaactct tcccactccc    420
agaatccaga agtaagctct gcatgttccc cttcctggga ggaaaccaat tgtcagaagg    480
atgtatgatg accccctccc tcccatcc                                       508
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 48
<211> LENGTH: 546
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  48
gagtcccccc acgcttccgc ccacgcgtcc gcccacgcgt ccgttttttt tttttttttt     60
tttttatttt tacaaagttt tattgaaact tgtccatcaa ggtgacagta attcactgtt    120
ttgaaaagtc acaaaaaagg gtacccccaa actcaggtat accaagtaaa tactggaacc    180
cagggagctc actcctccct ctcccaccag gagcaaaggg cataacggga gcttccgctg    240
actcacagca acctgggcta gtgggtacat ctgtggcgac tcccgggaaa ctgagctgcg    300
tataaagaag tctgctttgg tccaaaggac atcttcctga cccagactca gaaggctgct    360
gtcaagttct acattccttt cagaataagc aacagcaact gctgcantct tgctaactaa    420
gggcanaagt cctgaacaag gtgccacggg aacttgttaa atcacgctgt gtgattttat    480
agggaaaaag gcanaatgct ctcaantttt cacggttaac actgtcncta ttatgantgg    540
aataaa                                                               546
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 49
<211> LENGTH: 191
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  49
accacgcgtc cgcngacgcg tgggcggang cgtgggtttg cttctcggtt atcctgtgct     60
tcagaagaac cnaaacaaat cnattnncan atgtcttact nnaccangtg tgtcacccaa    120
gatncnntan nccacnanaa atcaacnanc accncacnag tngtngtnan ancnntacat    180
aggtgggaat g                                                         191
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 50
<211> LENGTH: 212
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  50
ccggaattcc cggggtcgac ccacgcgtcc gcccacgcgt ccgctgatga cctggatttt     60
aagcaccaca attataagga aatgcgccag ttgatgaaag ttgtgaatga aatgtgtccc    120
aatatcacca gaatttacaa cattggaaaa agccaccagg gcctgaagct gtatgctgtg    180
gagatctcag atcaccctgg ggagcatgaa tc                                  212
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 51
<211> LENGTH: 71
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  51
aatacccggg tcgacccacg cgtccgccca attggaccaa tctatcaccc tatanaagaa     60
ctaatgttag t                                                          71
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 52
<211> LENGTH: 306
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  52
ctggcgtgct ggacgaattc ggaaacacct tggtcttact tccctaaaat ctccatctac     60
ctgagagatg agaactccag caggtcattc cgtatcacaa tcctgcctca gctttacatt    120
cagcccatga tgggggccgg cctgaattat gaatgttacc gattcggcat ttccccatcc    180
acaaatgcgc tggtgatcgg tgccacggtg atggagggct tctacgtcat cttcgacaga    240
gcccagaaga gggtgggctt cgcagcgagc ccctgtgcag aaattgcagg tgcttgcagt    300
gtctga                                                               306
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 53
<211> LENGTH: 262
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  53
gtctccacca ccgctgctgc aacccctgct gctgctnctg cctctgctga atgtggagcc     60
ttccggggcc acactgatcc gnatccctct tnatcgagtc caacctggac gcaggatcct    120
gaacctactg aggggatgga gagaaccagc agagctcccc aagttggggg ncccatcccc    180
tggggacaag cccatcttcg tacctntntc gaactacagg gatgtgcagt attttgggga    240
aattgggctg gggacggctt ca                                             262
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 54
<211> LENGTH: 205
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  54
tgcnttccan ttgttggttg ttccaacncc cccatgttcc taaccnntnc ngattcccgg     60
ttnccaaccc naaataatcc ccctccggtt ccncctncan taaatccccn ggcnccgggc    120
nttcggtggc gggaaaacgg ttttnctccc tccaaagggg ggtatncngg tttnccccaa    180
aaccggggaa aaccccngaa aaaaa                                          205
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 55
<211> LENGTH: 1363
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  55
gcatcttggg aagaacccgc cggcgattga ctgtctttgc aagaaatatg atacgagcac     60
agaagattca ggccctggac cgcggcacag ctcagtatgg gatcaccaag ttcagtgacc    120
tcacagagga ggaattccac accatctacc tgaatcccct cttacagaag gagtctggca    180
ggaagatgag tccagccaag tccataaatg atcttgcccc gcctgaatgg gactggagga    240
agaaaggggc tgtcactgaa gtgaagaacc agggcatgtg tggctcctgc tgggcctttt    300
ctgtcacagg caacgtggag ggccagtggt tcctgaaccg ggggactctg ctctccctgt    360
cagagcagga gctcttggat tgtgacaagg tggacaaggc ctgcttgggt ggattgccct    420
ccaacgccta tgcagccata aagaatttgg gagggctgga gacagaggat gactacggct    480
accagggcca tgttcagacc tgcaacttct cagcacagat ggcaaaagtc tacatcaatg    540
attcagtgga gctgagccgg aatgaaaata agatagcagc ctggctggcc cagaaaggac    600
ctatctcagt tgccattaac gccttcggca tgcaagttct atcgccaggg gattgttcaa    660
cccattccgg cccttctgca gcccttggtt catcgaccat gctgtgttgc tggtgggcta    720
tggcaaccgc tctaacattc cttactgggc catcaagaac agctggggca gtgactgggg    780
tgaggagggt tactactact tgtaccgtgg atctggagcc tgtggtgtga ataccatggc    840
cagctcggcg gtggtggact gaagaggggc ccccagctcg ggacctggtg ctgatcagaa    900
gtggctgctg ccccagcctg acatgtgtcc aggcccctcc ccgggaggta cagctggcag    960
agggaaaggc actgggtacc tcagggtgag cagagggcac tgggctgggg cacagcccct   1020
gcttccctgc accccattcc caccctgaag ttctgcacct gcacctttgt tgaattgtgg   1080
tagcttagga ggatgtcagg gtgaagggtg gtatcttggc agttgaagct ggggcaagaa   1140
ctctgggctt gggtaatgag caggaagaaa attttctgat cttaagccca gctctgttct   1200
gcccccgctt tcctctgttt gatactataa attttctggt tcccttggat ttaaggatag   1260
tgtccccctc catgtccagg aaacttgtaa caaccctttt ctaacagcaa aaaaaagatg   1320
tccttataaa aaaaataaaa aaaaaaagaa aaaaaaaaaa aaa                     1363
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 56
<211> LENGTH: 418
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  56
ttttcaatgt gaggagttaa tttatattta attctaaagg tgaacgatgg ggacaagctg     60
tgtcatatgg tccacaactg ccacagctca gttattttgg attacatttt caatccaggg    120
tatatagtaa aaaattttgg catagatgcc aacatcagct ctcaaaacac atccatccgc    180
aaaagacagg attccttgaa gcatcccatt gcagattgcc ggggcagcag aaacttcctt    240
gcagggctgc ctccttcctg gcacaatgcc cacacacagc atattttccg tgatgttgta    300
ggttttatag gcatcgcgac actgaggctt ggagattaca gagatgttca cagtttgcag    360
tgaatcgggc tctttgtaga tatcacacac attgtagctc caggtagaga cagagcan      418
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 57
<211> LENGTH: 654
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  57
ccctgcgccc cagccaggcc tgaggacatg aggcggccgg cggcggtgcc gctcctgctg     60
ctgctgtgtt ttgggtctca gagggccaag gcagcaacag cctgtggtcg ccccaggatg    120
ctgaaccgaa tggtgggcgg gcaggacacg caggagggcg agtggccctg gcaagtcagc    180
atccagcgca acggaagcca cttctgcggg ggcagcctca tcgcggagca gtgggtcctg    240
acggctgcgc actgcttccg caacacctct gagacgtccc tgtaccaggt cctgctgggg    300
gcaaggcagc tagtgcagcc gggaccacac gctatgtatg cccgggtgag gcaggtggag    360
agcaaccccc tgtaccaggg cacggcctcc agcgctgacg tggccctggt ggagctggag    420
gcaccagtgc ccttcaccaa ttacatcctc cccgtgtgcc tgcctgaccc ctcggtgatc    480
tttgagacgg gcatgaactg ctgggtcact ggctggggca gccccagtga ggaagacctc    540
ctgcccgaac cgcggatcct gcagaaactc gctgtgccca tcatcgacac acccaagtgc    600
aacctgctct acagcaaaga caccgagttt ggctaccaac ccaaaaccat caag          654
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 58
<211> LENGTH: 421
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  58
gcgtccgctt ggcttcagtt cagatttcaa gctgtgttgg tgttgggacc agcagaaggc     60
aaacgtccag ccaacacaca ggactgtaag aggactctga gctacgtgcc ctgtgaagac    120
ccccaggctt tgtcatagga ggtcgttcag cttccccaaa gtcagaggtg atttgatttg    180
gggaagactg aatattcaca cctaagtcgt gagcatatcc tgagttttac ttccttatgg    240
cttgccctcc aagttctctc tctcatacac acacacaccc ttgctccaga atcaccagac    300
acctccatgg ctccagctat gggaacagct gcattggggc tgcctttctg tttggcttag    360
gaacttctgt gcttcttgtg gctccactcg cgaggcagct cggaggtgtg gactccgatt    420
g                                                                    421
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 59
<211> LENGTH: 865
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  59
gtccgttttc ttttagaaat aatgtattgt gtctgtgcag aaaaaaaaaa accaaaaagg     60
attgctttac tccaagagga gagattgtct taggataaac ctccaagctc acatttaata    120
taacagactg aagtaaacat tagaatcctg tttagagcta ttctgcacag ttaactactg    180
atctttagaa tctaaaattg tatatgaact tattcttaaa taattgaacc gttttatatt    240
caaatgactt atgatcgtgg ttagtttggg aaaaataaga tggttaaatt ttgatttatt    300
gaaatgtaat tgtattattt tcataaaata gcattttcat ttgtaatgtg gtttaacatc    360
cttgttgttt gccaaagaaa tttcatttgg ctgtgaatat tctatttgct tgcagtatct    420
gtttctcttc ctaggctcaa gttggtgacc caagcctatt gtaaacaagt gattatctca    480
aagggagatg ccaatggagt aacaatttgt taaccttacg ttttctgtct gtatattttt    540
ttaaaaatct ggtagtttct ggaaaaaaaa gagaaggggg tttgtagtac ttaaccctat    600
ttatttccgt atattttagt taattagttt ttggaataaa tggatttcag tatagctttg    660
tggttaaatt gcattgcctt tattttatgt ttaggcttat ttttaaatta acatttaaca    720
gaaacatttg aaatagaatt tgcatgtctg ccttaattaa cttaaagact gattttaatc    780
tgactatgac actgagcata ttctttaaat tactcataat ttataatgct taatataatc    840
ttaattaaat taagcagttt tagtt                                          865
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 60
<211> LENGTH: 388
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  60
agtgagcaga caccactcga cttcctttct gcgtcaccag tgtcgtcagc agagagagga     60
cagcacaggc tcaaggttgg tagtgaagtc aggttcgggg tgcatgggct gtggtggtgt    120
tgatcagttg ctccagtgtt tgaaataaga agactcatgt ttatgtctgg aataagttct    180
gtttgtgctg acaggtggcc taggtcctgg agatgagcac cctctctctg gcctttaggg    240
agtcccctct taggacaggc actgcccagc agcaagggca gcagagttgg gtgctaagat    300
cctgaggagc tcgaggtttc gagctggctt tagacattgg tgggaccaag gatgtttttg    360
caggatgccc tgatcctaag aagggggc                                       388
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 61
<211> LENGTH: 549
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  61
gaccacgcgt ccgaagccca gcacgctgca ggtcgatcta ttgcaggaat atttccattg     60
gtggtgtgct tgtcccactg gaactgaagt ctaaagagcc tgatggggac agagttgttt    120
atacgggtac atatgacaca gaaggtgtga ccccaacgaa gagtggagaa cggcaaccca    180
tccagatcac catgccgttc acagacattg ggaccttcga gacagtgtgg caagtcaagt    240
tctacaatta ccacaagcgg gatcactgcc agtggggaag ccccttctct gtcattgagt    300
atgaatgcaa gcccaacgag acaccgcagt ctgatgtggg tgaacaagga gtccttcctc    360
tgaaagtggc tctttctgat gctactggac aatcttttca gaaatctact tttagataaa    420
ccagcgcagg ccttaaacaa ggcatgccac accattgctg ttccccatct ggtactaatg    480
acctactagc cctggttatt ttgaaagtgt aattcccctc tgacacaata tccctcacat    540
acaagatgg                                                            549
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 62
<211> LENGTH: 230
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  62
ggggccgagg ctgctccaac cctctgtacc ctggagtgta tgccagtgtt tcctatttct     60
caaaatggat atgtgataac atagaaatca cgcccactcc tgctcagcca gcccctgctc    120
tctctccagc tctggggccc actctcagcg gcctaatggc catgctggct ggctggtcag    180
tgctgtgagg tcaggatacc cactctagga ttctcatggc tgcacaccct               230
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 63
<211> LENGTH: 865
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  63
ttttttgcta cattcccaaa ttttcatttg gagattttat tttgaataga gggaaaatta     60
tctgcttgta tagtccatgg cagagcacgt ggaatgcaga gggagaagta gggtctcact    120
tgtccttagc agtgttctca atccaggata catatttgta aacattggtg tagatgccga    180
cgtcccctcc catgaagtgc cccacctcga ttccctggag cttgtctttg cagatgacag    240
tagcaacggc cacctcccca aaaattcggc tgaatacttt cacaaatttc acacataagg    300
aattcctgtg gctttttcct tgttctgttt tttggcattc tcgatcagac atcacggggg    360
cctccaggtt ctgccgcaag tcagggtgtc ggccactgtt ttccttggct cagtccaaac    420
ctgagagtag acagacagtg cccggcctga cattggtggt ggcgaagggt aaggggctgg    480
actttgggat tgagcatggc aggcttagcc agcttgatga gcatgaggtc atcctgtggg    540
gcgctatgac tgtagttcca gtagcggacg atctgaatgg ggttaattgt ctgttcagta    600
ccgtctctga ctctgctctt gaaatttccc agcatcactt tcagatttgg taaatagcag    660
tgagctgggg ccagcaccca gctgggtttg atgaggacgc ccacacaggg gttgaagtga    720
gacttgaggt acaccaaata gggagcaggg tcttctttct gaacagatga gtcagcaaag    780
aaaaatgtcc cagcgaggac acccaaatag aagacatatt tcatggtgat ccagctcttc    840
ccccttagct cagggagtaa gtgcc                                          865
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 64
<211> LENGTH: 452
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  64
caaaaaggag accagacagg aggcgtctgt agagatatca tgaacttcaa cttagctttg     60
ttttccagag actggagcta aactgggctt tcaacatcat catgaagttt atcctcctct    120
gggccctctt gaatctgact gttgctttgg cctttaatcc agattacaca gtcagctcca    180
ctccccctta cttggtctat ttgaaatctg actacttgcc ctgcgctgga gtcctgatcc    240
acccgctttg ggtgatcaca gctgcacact gcaatttacc aaagcttcgg gtgatattgg    300
gggttacaat cccagcagac tctaatgaaa agcatctgca agtgattggc tatgagaaga    360
tgattcatca tccacacttc tcagtcactt ctattgatca tgacatcatg ctaatcaagc    420
tgaaaacaga ggctgaactc aatgactatg tg                                  452
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 65
<211> LENGTH: 197
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  65
ttntgtttaa atatatttac aatgtnttct gctctattct ttagtagact tttcctcacg     60
tggtcntacg catttctttc taagtttatt ttcatatagc ctatccctgt ctacaattta    120
aattgggatc ttctatattc tagttattat ttgtaaataa gaaaactact gacttttttc    180
tagtatatnn tctcaga                                                   197
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 66
<211> LENGTH: 492
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  66
tttttttttt tttgggggga aggaaacata ttatttggaa tcaaaggaca ataatacgtc     60
aagcaccaaa tgctacaaag aaatcatgaa aataggcctt aaacgagtca ttcctagatt    120
aacctcccca catgtgaaaa taagtcttgg aagtagaaag ggtgggtttg gttctggtcc    180
ctagagatga caacgtgcag tgactgcagt tctgcacttc tcccctggtg cgtcttttct    240
gagtggctgt tggtggcttt gcacgtgagg tcacataact gcttatctcg tcaggaattt    300
tgcaagaccc ctggagagaa aaccagatgg accagtggga aaggccgccc ttgcaagttg    360
ctgcttcttt tgttcttagt gaagatcaga aacgaaggag gtgacaccgg tgtacacccc    420
aggcttgttc acctctgcgc agcgaatgcc aaagctggtc ggtcccacta acttccacag    480
gctcctctct tg                                                        492
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 67
<211> LENGTH: 460
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  67
gtccgcggac gcgtgggatt ttttgaagta tttttgccaa ctaaaatgaa gtctgtaaat     60
tctgttaata aacaaggagt tcatccgttg ctcacatctt tcattggtgc cctctgaact    120
ctgtgggttg ctaggatgta attttaatgc ttccctgcag tccaaagatg attttttcac    180
cacaaatggt aagggatgcc cacctacttt tataaacacc actgcaactt aacaagttta    240
tttatctatg tccagatttc tgtttctgtc ctaaattgat ctggtgtttt taggtggatc    300
aacttggatc tttagacctc atctataaat tgaaattata tttttagtca taagccaagt    360
acaatctaac tcagaatggg attaaaaatt ttagaagcag aagctaatat ataaatgaag    420
tttgggattt ggaactttct gtatctctta agaagaacaa                          460
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 68
<211> LENGTH: 700
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  68
ttgagcccgc actcgcagcc ctggcaggcg gcactggtca tggaaaacga attgttctgc     60
tcgggcgtcc tggtgcatcc gcagtgggtg ctgtcagccg cacactgttt ccagaagtga    120
gtgcagagct cctacaccat cgggctgggc ctgcacagtc ttgaggccga ccaagagcca    180
gggagccaga tggtggaang gccagcctct ccgtacggca cccagagtac aacagaccct    240
tgctcgctaa cgacctcatg ctcatcaagt tggacgaatc cgtgtccgag tctgacacca    300
tccggagcat cagcattgct tcgcagtgcc ctaccgcggg gaactcttgc ctcgtttctg    360
gcttggggtc tgctggcgaa cggcagaatg cctaccgtgc tgcagtgcgt gaacgtgtcg    420
gtggtgtctg agggaggtct gcagtaagct tctatgaccc gctgtaccac cccaagcatg    480
ttctgcgccc ggcggagggc aagaccagaa ggacttctgc aacggtgact ctggggggcc    540
cctgatctgc aacgggtact tgcagggcct tgtgtctttc ggaaaagccc cgtgtggcca    600
agttggcgtg caggtgtcta caccaacctc tgcaaattca ctgagtggat agagaaaacc    660
gtccaggcca gttaactctg gggactggga acccatgaaa                          700
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 69
<211> LENGTH: 417
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  69
ttttcaggtt ttcaaagctt tatttctcca gcaccacctt tatccagaag gtggttcata     60
gccccctgca aattgtaaac caatattgct cttttaaatt taatagaaag tcttctgcat    120
tgtttatgta tataagtgca gaaatttagg attattttgg accatcaaca aggaagttgc    180
tggattcttt gactttctta cgttgtaatt tgcttacttg ccaccgatac aggtgagaag    240
ggccaaacac ataatagtgc atgaagactt taacacacta agttatgact ctgacattgc    300
cctaatacaa ctaagctttc ctctggagta caactcggtg gtgaggccag tatgtctccc    360
acacagcgca gagcctctat tttcctcgga gatctgtgct gtgaccggat ggggaag       417
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 70
<211> LENGTH: 502
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  70
cgcgtccgca aagactgtga ggagaggaga gtaagtataa gaatgagcat tgaactacaa     60
tcagtttcta atccagttca cagaaaggac ttagttattc gtctgactga tgacacggat    120
ccattttttt ttatataacc ttgttatatc tgaggaagat tttcaaagtt taaaattcca    180
gcaaggtctt ctggtagact tnttagcttt cccacaaaaa tttatagatc tccttcagca    240
atgtactcaa gaacatgcca aagaaattcc aaggtttttg ctacagttag tttctccagc    300
agctattttg gataactcac ctgcattttt aaatgtggta gagacaaatc cttttaagca    360
tcttacacac ctctcactaa aacttttacc tggaaatgat gtggagataa agaaatttct    420
cgcaggctgt ttgaaatgta gcaaggaaga aaaattatca ttgatgcaat cctagatgat    480
gctactaagc aactggactt ta                                             502
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 71
<211> LENGTH: 614
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  71
tttttttttt aatcaaaacc atctttatta tttaaagagc attccatcat gcacggggca     60
cctagacagg agtcccccac tagcacagca atattaacat gggggtcagg agggggaggt    120
tgggtggcct cggggcttag tggacccgcc actgtggaat acaggaccct ggagggaggg    180
tgtccttcaa cctgtggacc gggcccaata ataaaaactt tccatcctcc gccctatcgt    240
ggatcccacc accgggatca ccttgggccc tggagggtgc gcagcgagaa aaccacccgg    300
tccagagctg tgtcattatt gtcgctggct tctggatttt attctttatg gtctggaata    360
ttcactcccg gaagtcactg actttggtgt agacgcctgg cttctgggcc aaggcacagc    420
cagtgcaacc aactcacaat gccacacagc cgcaaacgtg gcgtccgaga gatgctgtcc    480
tcacacgcaa agggaccacc gctgtcgccc tggcaggcat acaatgccac ctgcgggtag    540
gccagcacag aacatcttgg ggcttgatct ggttgtccat agaagtcagc gccattgcgg    600
acatcaatgc tgat                                                      614
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 72
<211> LENGTH: 506
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  72
tttcagcatt ttcaaagcac tttattgagt tcctgcgcca tcctggcann gctggccgca     60
ctgggggaat gggacacaat cttgccttcc atgccccagc cactctctca ctgcggaatc    120
accaaggagg gaaagatgag tccctgagca atcaggaaac ggtgtgctcc cggatccagg    180
ccaggtagta gggcacatcg gtgtagacgc ctggcttgtt gcggtcacca cagcccgatc    240
ccccagctga tgatgccttg cagggttgag ccggcgctct gcaactttgg ttcctcacac    300
accagcgggc ctccggaatc accctggcaa ggcatcggtg cgcccctcga ggaaccctgc    360
gcagagcatg ccggggaaga tggaggatcc gtgcacgtcc ggggctgagc agcgcccagg    420
ggagaggaag gttacctgcg cttcctgcag gaagctggca tattccttcg ccccttcgga    480
ctggttggcc ccagcgggcc aactgg                                         506
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 73
<211> LENGTH: 463
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  73
tatacaacac gaccctacga gaagcagaga cctaccgcat gagggtccga gcctcatcct     60
acagtgccaa tgggaccatt gaatatcaga ccacattcat agtttatata gctgtgtccg    120
cctatccata ctaaggaact ctccaaagcc tattccacat atttaaaccg cattaatcat    180
ggcaatcaag cccccttcca gattactgtc tcttgaacag ttgcaatctt ggcagcttga    240
aaatggtgct acactctgtt ttgtgtgcct tccttggtac ttctgaggta ttttcatgat    300
cccaccatgg tcatatcttg aagtatggtc tagaaaagtc ccttattatt ttatttatta    360
cactggagca gttacttcca aagattattc tgaacatcta acaggacata tcaagtggat    420
gggttacagn agtggtagga cctaaagaac attttcctga agg                      463
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 74
<211> LENGTH: 126
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  74
taaatgaata ttatgtgtaa ttgtttcaaa catccatttt ctttgtgaac atattagtga     60
ttgaagtatt tcgactttng agattgaatg taaaatattt tanntttggg atcatcgcct    120
gttctg                                                               126
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 75
<211> LENGTH: 249
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  75
gagtgggatc tcactttaat ggagaggacg ttatgacctc cggggcatgg ctcttggcgt     60
tgggaagccc ctggttttca tggacctgtc gatccacttg aggaaggcgg tgaccttggt    120
gtagatcccg tacttcccct tacgggcaca gcctctcccc agctgaagaa gcctgtcacg    180
aagtagggtg tcctttaagc gggggacgtg tgggcccccc ttgttccccc tggaggggta    240
ctcctcctt                                                            249
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 76
<211> LENGTH: 487
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  76
cactttaggg agtcgaccca cgcntccgcg gacgcgtggg ttttcaaact gacaatgttt     60
aggttttaag caaataaagt tccagttaat gtgaaactca gtcacaaaga gttgagattt    120
ttcctttatg aaatagaatt gacattcttt tatgctataa atgtgcattc aggtcccatt    180
aaccatgctc tgcttttatt tggggataga acattttctt tttcatatcc cgatcttccc    240
atttcttcat agaaatgtga taagaagtac atccctgtga tcctgctgct tcgtagagca    300
ccactgcaca ccctaccccg agtgccaacc acctctgcta taggacacta ttttcctggc    360
cctattcttc acttacttcc catcctgtcc ttgactagga atatgttaaa tgctgctccc    420
atacaattca gttagctctt gtctttttat ttggtccaac ccctgcttta ctgctcatgc    480
tgcttaa                                                              487
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 77
<211> LENGTH: 474
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  77
tcaccagatt taaaggggat tgcagacatc atgattgcct ttaggactcg aggattcaac     60
ttgtttcttg tggctgctca tgaatttggt catgcactgg ggctctctca ctccaatgat    120
caaacagcct tgatgttccc aaattatgtc tccctggatc ccagaaaata cccactttct    180
caggatgata tcaatggaat ccagtccatc tatggaggtc tgcctaaggt acctgctaag    240
ccaaaggaac ccactatacc ccatgcctgt gaccctgact tgacttttga cgctatcaca    300
actttccgca gagaagtaat gttctttaaa ggcaggcacc tatggaggat ctattatgat    360
atcacggatg ttgagtttga attaattgct tcattctggc catctctgcc agctgatctg    420
caagctgcat acgagaaccc cagagataag attctggttt ttaaagatga aaan          474
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 78
<211> LENGTH: 1687
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  78
gtctnnnnnn nnnnnnnnnt tnttttttnt agaattgcta aagattggtt taataaatgt     60
ttcagtattc agttataaga catgtcttct ccaagtccac aaagcatgaa ataggcttaa    120
agtacagtca gagatttttg tttctacata ataacttcct attaaaagaa tcaggcagct    180
caaaatggcc attgaatttg gatatttaga actaggacca gcaacttgtt gttaaagaat    240
ggttttattc tattttgaag cagaatttat attaaaagac ctgttgaggt ttattttagg    300
tctatgaatt tattgataaa tagaagtgtt tttcagcaaa tgaacaatac caaaaataaa    360
caagcttaaa ctcttatgat acaatatctt tatgcctcct gaatgtgctt tttccttgtt    420
gatatcaaaa ccaaatgagg agttctttgg ttctttgcat tgaaaccaag tattagttct    480
catgattcgg gtaatattct ttgtcttaat gttgtattca aattgctttg atccacggct    540
gaaaaagaag aatcctttgt actggaaagc agcatcaaca cggatactga ttccaggaaa    600
gtgttttacc actctctgcg ggaatccttt gtccatggtt tgggtcattt catcaaacct    660
ccagcaccaa atgcccacaa agaagtaggt ttttcttgtg gtcttatcac agacggctgc    720
atctattttc ttcacacggt cctggaaaac ctaatgtatg gatggatttg ggataatctg    780
gcaagacagc atatcctctg atcatccaga agttttcatc tttaaaaacc agaatcttat    840
ctctggggtt ctcgtatgca gcttgcagat cagctggcag agatggccag aatgaagcaa    900
ttaattcaaa ctcaacatcc gtgatatcat aatagatcct ccataggtgc ctgcctttaa    960
agaacattac ttctctgcgg aaagttgtga tagcgtcaaa agtcaagtca gggtcacagg   1020
catggggtat agtgggttcc tttggcttag caggtacctt aggcagacct ccatagatgg   1080
actggattcc attgatatca tcctgagaaa gtgggtattt tctgggatcc agggagacat   1140
aatttgggaa catcaaggct gtttgatcat tggagtgaga gagccccagt gcatgaccaa   1200
attcatgagc agccacaaga aacaagttga atcctgctcc atccttggtc cagttttcat   1260
cctcatcaaa atgagtgtca ccacccagac ccggaccagg aggaaaggca tggccaagca   1320
ctcccaaggg accatcaaaa tagcgaggac accgaccatg gactcgagtc ctaaaggcaa   1380
tcatgatgtc tgcaatcccc tttgaaatct tggtgaattt tagtggagtg actttgctcc   1440
acacttctaa accttcttgg atagcctcat ccacagcagc tcgtgccata tccggagtat   1500
agtttattat tctgtaggtg aggttgtatt ttctccaccc agggagggtg tagccatact   1560
ggcccacatc aggcacccca cacctgggtg tcttcatgat ctcaagggtg tttgagtcca   1620
gttttccagt cactgtcaat ccaaaaaatg cttgcatttc ccgaattttg tcatctcgga   1680
cgcgtgn                                                             1687
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 79
<211> LENGTH: 542
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  79
gttgatgata aaaacttaaa accaggacct ccattctgtc atgactgaca ccatggtagt     60
ctgtcagctt gaccagtgga gagtcattca tttagcacaa gcagctggag atttaaactg    120
ccagtactat gtatttggtg tataatgcaa ggaagaaact ttatccttga atttgagggt    180
gatggggtgg gtcaggaaag gatggcgcca gaattctaca tgataatgaa ctaaaaaatg    240
ttgcttttca gaggaagata aagcatcttc ttttgggagg gggggtatct catgtctaag    300
taagtaaaag aaagaagtag ctactgtctc ttttaaaaac cacgtacaaa acagaacaag    360
tctcagtttt cagtgcaaca tttcaaaaaa tatatatgct gcaatctaat aattaaaagg    420
aattttacct attatgaaac ttattacatt tnttaaggta ggataatcag nttcaaagga    480
gtattcaggg tatttaactt ggttttaaat ggctgctcaa aaaaaaatgn ctattttttt    540
tn                                                                   542
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 80
<211> LENGTH: 265
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  80
ctggtcctgg atgcaccgca cccgcatagc aggtggctgc tgcactacca aggcatacgc     60
tgcgtggaag ccaccctaag ccacagacag cggatcttcg gagtccgcca gcgcggcctc    120
caacggcact cccacagacc caagatcgga tccgaggtgg aactgtagac actcctgagg    180
tgacccggct agatcggccc tgcccaaggc taaccaccag agactgcgat gggcacactg    240
gtgggcagct gagggcactc cgcca                                          265
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 81
<211> LENGTH: 510
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  81
atgtattcac caagcatttt acggatttga ctttttcact aaccagttga cgaagcagtg     60
catttacaag gcactgccaa acaagatgcc cttgggagct gtgagggaaa gaggacctgc    120
gggcttagat caatctcaat tccttttcat gccctcctgc attgctgctg cgtgggtatt    180
tgtctcctta gccatcaggt acagtttaca ctacaatgta agctataggt ggagcatcag    240
cagtgagtga ggccattctt catccttagg atgtggcaat gaaatgatgg tgcaagttcc    300
tttctctttt gtgaatcttt ccccccattt cctgtttaca tgtaacccaa caaaatgcaa    360
tttctagtgc cttctgtcca atcagttctt tcctctgagt gagacgtact tggctacaga    420
tttctgcctt gttttgcgac attgtcccat tcacacagat attttgggat antaaaggaa    480
aataagctnc aaaaaaaaaa aaaaaaaagg                                     510
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 82
<211> LENGTH: 798
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  82
tccgggnccc cctnaaggag cangctttac aggaggactg gagccagtgc accctgccan     60
nctcccggac tcctctctgg caaccagtgc cccgctgtgc tgcaccctct gccacgaagc    120
ggctggagga cacccntttn gtgcattgcc cgtccgtccc ttcncacaat tnctgctncc    180
ctngctccaa acaaancntc aancaccagg nanctattga aaagntctnt tntcccattg    240
gggaaaaatg ccctcttgtg ggctccaatg tcccctgggc ctttatgcaa ggggaaattg    300
caaccatcct tgctggagat gtgaaagtga aaaaagagag agactcgtga cttttccggt    360
ttcaaaaaaa acccaatgat taccccttaa ttaaaactgc tttgaaattg tatatatatc    420
tccatatata tatatatcca agacaaggga aatgtagact tcataaacat ggctgtataa    480
ttttgatttt ttttgaatac attgtgtttc tatatttttt ttgacgacaa aaggtatgta    540
cttataaaga catttttttc ttttgttaac gttattagca tatctttgtg ctttattatc    600
ctggtgacag ttaccgttct atgtaggctg tgacttgcgc tgctttttta gagcacttgg    660
caaatcagaa atgcttctag ctgtatttgt atgcacttat tttaaaaaga aaaaaaaagc    720
caaatacatt ttctgacatt gtaaaaaaaa aaaaaaaggg cggccgctcg cgcccacgcg    780
tccgcggacg gggggcgn                                                  798
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 83
<211> LENGTH: 712
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  83
naaaggcttc tgtagaganc atgctgggtc tgcatctcct ctcgtctcct ccatggtggt     60
cactgcccct ggcaggtctc tgaaagggaa atgctttttc ccagaggccc ctgcttgggc    120
agttcacagt gagaccgacc ccctctgaat atgataacag cctgtttcac atgaggagat    180
gttaccaatc ccgttcgctc tgacccttgc tggctgatca ccttgagcaa cttacttaac    240
atctgtgttc ctcagtttct catgggtaat atagggataa ttactggcac ctgcctccca    300
ggccattctg acgtgtaacc gcatatagga gcccactggc tgagtagcta ccatcatcgc    360
tggtggggaa actggtggta ggggtgtagg tatttggggg gggttgttca gccccccagg    420
tgtttcagaa caaggcctcg ggcactccca agtctgcctt ttggctccca ccctcaaagc    480
ccatgttctg tgaggcccaa gaaaaacaca tggagttctt agccaaatgc actaatgtat    540
tcccggggga actgtcacct tggccaccac ctggggccac tcctgcttgg ctacaactcc    600
atacttcctg ttggttggca ttgggaanaa tttcccccca tgaatgaang gccccaagaa    660
atanaaatct tgttaccact ccanttgcta ccaatccccc caccccctac an            712
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 84
<211> LENGTH: 317
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  84
tgaaggagct gaaggaggcc ctgcagctga acagtactca cttcctcaac atctactttg     60
ccagctcagt gcgggaagac cttgcaggtg ctgccacctg gccttgggac aaggacgctg    120
tcactcacct gggtggcatt gtcctcagcc cagcatatta tgggatgcct ggccacaccg    180
acaccatgat ccatgaagtg ggacatgttc tgggactcta ccatgtcttt aaaggagtca    240
gtgaaagaga atcntgcaat gacccctgca agagacagtg ccatccatgg aaacgggaga    300
cctctgtgcc gacaccg                                                   317
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 85
<211> LENGTH: 1021
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  85
gcggacgcgt gggcggacgc gtgggcggac gcgtgggtcc gggtggccgc ggccacgaac     60
cgcgtagttg cgcccacccc gggacccggg agccctgccg agcgccacgc cgacggctng    120
gcgctcgccc tggagcctgc cctggcgtcc cccgcgggcg ccgccaactt cttggccatg    180
gtagacaacc tgcaggggga ctctggccgc ggctactacc tggagatgct gatcgggacc    240
cccccgcaga agctacagat tctcgttgac actggaagca gtaactttgc cgtggcagga    300
accccgcact cctacataga cacgtacttt gacacagaga ggtctagcac ataccgctcc    360
aagggctttg acgtcacagt gaagtacaca caaggaagct ggacgggctt cgttggggaa    420
gacctcgtca ccatccccaa aggcttcaat acttcttttc ttgtcaacat tgccactatt    480
tttgaatcag agaatttctt tttgcctggg attaaatgga atggaatact tggcctagct    540
tatgccacac ttgccaagcc atcaagttct ctggagacct tcttcgactc cctggtgaca    600
caagcaaaca tccccaacgt tttctccatg cagatgtgtg gagccggctt gcccgttgct    660
ggatctggga ccaacggagg tagtcttgtc ttgggtggaa ttgaaccaag tttgtataaa    720
ggagacatct ggtatacccc tattaaggaa gagtggtact accagataga aattctgaaa    780
ttggaaattg gaggccaaag ccttaatctg gactgcagag agtataacgc agacaaggcc    840
atcgtggaca gtggcaccac gctgctgcgc ctgccccaga aggtgtttga tgccggtggt    900
ggaaagctgt ggcccgcgca tctctgattc cagaattctc tgatggtttc tggactgggt    960
cccacttggc gtgctggacg aattcggaaa caccttggtc ttacttccct aaaatcttca   1020
n                                                                   1021
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 86
<211> LENGTH: 751
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  86
cattataaat aaataaaang caaaatctgt tgtacatata tttgtacatc tatgcatttg     60
ccttgcntcc tccttattgt aaatggcata tttatgactc tttgcatatt gtaatcacaa    120
ttntggaaaa tggatatcat agtaaaaaat acagtcttct atatttgctt ggggttacag    180
gtgccccgcg tccggctcca ttattaaacg ggctgaaaat tgttgtgtgc taataatttt    240
aaaaatcaaa atcatgaaac aaaagaaaaa aaagaaagac aatgttacaa acaattaatc    300
tacaaaaata tttcagtgat tcccataatt taccttttag taatgtatac tatgttttca    360
atgagtttaa atgaattaac aaagaaaaaa acagaaaaaa gaaaacaagt ttgaatgttt    420
taggcaagtt gtagcgtaac tacattgtta tagttgagaa aattacaaat atcaataata    480
cataaagatg aaactaccaa agtaatacaa gttagataca atacttttcc acaaattaaa    540
acaaatgcaa cgatacaagc actatgtaag aatacattta gccgtgtgac tttcttttaa    600
tagggttatc agatctacga tataagataa atagatagta attcgacttt gccaacatga    660
attaaaatgc agatttcttt ttttctcaaa caaataatga tacgggtggt gcatctagtt    720
ttcaagacag gcgatgatcc ccaatttaaa n                                   751
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 87
<211> LENGTH: 895
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  87
ccgccccgcg tccggataag ccatttatta aaaggagtat ttactagaat tttttgtcat     60
ataaaacttg aatcaggatt ttatgcccca catactctgg aacttgaagt ataatatact    120
taatataaca taaaaagcca gttgggttct aaattgtagt tgaaacacag aaaatgccac    180
ttttctgttc ctgaagaggc tcttttgtgc ataatattct aaaatgaaga catttcaagc    240
tatacaaatt acttccaagt tttcatgatg tatgggaaga ttttcagtag gtgtattata    300
ttcacggtac caaatgctga ccagtgttgc tccatttttt aaatcttgaa aagggtttct    360
gtacttacct ggtttgccaa gtatgccagt gtaatgaaac tgcccttatt ttaaaagcca    420
gtcaaagatt ccactgattg acatttgata aataaacatc aggattatgt ttattgtttg    480
ttttcagtct ttgcactata ttaccagtat atggtttccg aggaagatta tctactgcaa    540
aacaccactg ttggaaaaat aggtattttt aaattgtttt taatcttttt tggtgctttt    600
aaacatgttt agcaaaaacc aattcagttc cattccccgc aaaaaacccc taactttact    660
ctgaactttt tttgtttttg cattccatga ggttctgtat tcagtcattc tctaggtaat    720
gtcatttttg tacacatata tttatataat cactgatttg agatttatga aaaagcattt    780
ctaaagaata tttgcttccc ttagaactac agactcgaaa tctttaaaga tggtgcctaa    840
gcatctatgt atttttttta agttccacag atttttctgt tgggcagcca aggan         895
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 88
<211> LENGTH: 172
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  88
tggatataca tctaaactgc cacttaatca tgaggacttg gcgcaagttg tatagagtgg     60
taatgatgtg ctattaactt ggtatgtcat gagctacatc tgtaggctta tagtatcaca    120
gagttatgag atatcaggtt agtcgttaga gtgtggctat gacctgggga tc            172
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 89
<211> LENGTH: 467
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  89
gtgtactcta tctgccacta aaggagagtc aaaggtataa ccagccctaa acttcgcagc     60
aatctattca aagttgctta acaggctctc tagaacgttc tagtaataat cctccagaat    120
ggagccatgt ttgtcctccg agcactctat ttcaaagcat tcagtcactc accctcgagc    180
agatgctgtg attttataag ttcctggaac caagagacgc cagtaatctc cagttttgta    240
agtagtcact gggtgattaa tctcagcaac actaatggtg gcatttaata tacccctgcc    300
atctgtggca tctagaacaa atcctctgac gccctgatga acctggatta agtacaagga    360
caccagattt caataataaa catcatcatc taattatctt gggaggtcat attcaaaata    420
acagattgtc aacacaaata aatggaacaa acagggattt aggagtn                  467
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 90
<211> LENGTH: 488
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  90
gtctggaaat acaaggttct aaanttcgga agagtttaga atttattagg agtttcccaa     60
gttgggatgt tagtctttaa ataaacttca tgcacctatt ccacttaagg ttttgcacct    120
cctttttatt agtgcagtgc catttcttct gcttgatttt aggtatgtta atattccagc    180
cttgctagtt agcataaagt gacaggtgtg agccatgagg aaattttctg acttaatttg    240
tacacaacta catataagag ttttagtgga ggaaaaaaat tagtcccttg tgcgtataca    300
gtagttaggt aaatgatttt tctaccaaca gtatactcca ttcctcatgt aggtaagtac    360
agaaaaggtt tttaaatgta tttttttagc cagttaaagt ctatgaatct atctgcaacc    420
ttatttaatc tgtcctataa taattttgtg gttatgctaa gaaccatgta tactttaggt    480
attcttat                                                             488
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 91
<211> LENGTH: 709
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  91
tagattgtct ctatttgagc agtaacatga ttgcaagaga ccaagtttca cagcttgtaa     60
agttctgtat ttgggattct tgcttatttt tccgcctgtg tttttctgag aacttattcc    120
tgatgatcaa ttgaatccag tagtttttct atgctatttg ttgntgtata agctactgta    180
agaaacttat cataaggaaa aatagaaagg aaaacttgaa tcaatactca ttgattaaaa    240
tggaataaag aaagagcagc tgccactttt aaacaacata aaggaatatc tttttttgtc    300
tccgtgtagg aaatcccata agttcttata tttgttccag ttcccatttc ctgccattga    360
ccagataaca tcattgactt tcaaatgact tttagaagtg ataactctta atttcctaat    420
agatactaga ttgtattgaa ttctgtttta attattctct aggtaagtat gttttaggat    480
taaatacctt ttacagatac tgaaagtgcc tccttttgtg gtgtaaaaaa caaattatgg    540
tgcaaaaagt aatcactaga ttgaaataca tgaaggtttt ttgctttttg acatacgaaa    600
atgtcaagag aaaggccaaa gatttgtact ttttcactta caaagcactc ctttttccct    660
taaacttctt tctgcaaatt agatttaatg agagagtact atttttaan                709
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 92
<211> LENGTH: 305
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboyxpeptidases
<400> SEQUENCE:  92
aggncccntt taagcaaacc gggagcagca tcgactgggc gtatgacaac ggcatcaaat     60
ttgcattcac atttgagttg agagataccg ggacctatgg cttcctcctg ccanctnacc    120
acatcatccc cactgcagan gatacgtggc tggggctgaa gaccatcntg gagcangtgc    180
gggacaacct ctactaggcg atggctctgc tctgtctaca gttatttgta cccncacntg    240
cacncactga ggccatagtt aaaggagcnc tttcctacct gtgtgagtca nanccctctg    300
ggttn                                                                305
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 93
<211> LENGTH: 673
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  93
ccgggacccc cgggccggat actgttcatt ggggccctta ttgggtccag catctgtggc     60
caagaaaaat tttttgggga ccaagttttt aggattaatg tcagaaatgg agacgagatc    120
agcaaattga gtcaactagt gaattcaaac aacttgaagc tcaatttctg gaaatctccc    180
tcctccttca atcggcctgt ggatgtcctg gtcccatctg tcagtctgca ggcatttaaa    240
tccttcctga gatcccaggg cttagagtac gcagtgacaa ttgaggacct gcaggccctt    300
ttagacaatg aagatgatga aatgcaacac aatgaagggc aagaacggag cagtaataac    360
ttcaactacg gggcttacca ttccctggaa gctatttacc acgagatgga caacattgcc    420
gcagactttc ctgacctggc gaggagggtg aagattggac attcgtttga aaaccggccg    480
atgtatgtac tgaagttcag cactgggaaa aggccgtgag gcggccggcc gtttgggctg    540
aaatgcaagc atcccattcc ccgaagagtn ggatctccca gggccactgc catcntggac    600
ggcaaaggaa gattggtntc ttgattacca gaagggatcc annctatcnc ctcccatctt    660
gggaaaaaat ggn                                                       673
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 94
<211> LENGTH: 1811
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  94
gaccncgcgt ccgcaatgac agtcggacct ggtggggaag ttggaaccac agcagtggga     60
tggacgcagt atttcctgcc aattcagacc cagaaactcc agtgctgaac ctcctgccgg    120
agccccaggt ggcccgcttc attcgcctgc tgccccagac ctggctccag ggaggcgcgc    180
cttgcctncg ggcagagatc ctggcctgcc cagtctcaga ccccaatgac ctattccttg    240
aggcccctgc gtcgggatcc tctgaccctc tagactttca gcatcacaat tacaaggcgt    300
ccgggaagct gatgaagcag gtacaagagc aatgccccaa catcacccgc atctacagca    360
ttgggaagag ctaccagggc ctgaagctgt atgtgatgga aatgtcggac aagcctgggg    420
agcatgagct gggggagcct gaggtgcgct acgtggctgg catgcatggg aacgaggccc    480
tggggcggga gttgcttctg ctcctgatgc agttcctgtg ccatgagttc ctgcgaggga    540
acccacgggt gacccggctg ctctctgaga tgcgcattca cctgctgccc tccatgaacc    600
ctgatggcta tgagatcgcc taccaccggg gttcagagct ggtgggctgg gccgagggcc    660
gctggaacaa ccagagcatc gatcttaacc ataattttgc tgacctcaac acaccactgt    720
gggaagcaca ggacgatggg aaggtgcccc acatcgtccc caaccatcac ctgccattgc    780
ccacttacta caccctgccc aatgccaccg tgactattta gtgggcggca gccgaactct    840
gtgggcggcc aaccttgtct cttgctcccg cccttcctga cccccaccac cccggtggct    900
cctgaaacgc gggcagtaat caagtggatg aagcggatcc cctttgtgct aagtgccaac    960
ctccacgggg gtgagctcgt ggtgtcctac ccattcgaca tgactcgcac cccgtgggct   1020
gcccgcgagc tcacgcccac accagatgat gctgtgtttc gctggctcag cactgtctat   1080
gctggcagta atctggccat gcaggacacc agccgccgac cctgcaacag ccaggacttc   1140
tccgttgaac ggcaacatca tcaaacgggg ctgactggca cacggtcccc gggggcatga   1200
atgacttcgg ctacctacac accaactgct ttgaggtcac tgtggagctt gtcctgtgac   1260
aagttccctt cacgagaatg aatttgcccc aggagtggga gaacaacaaa gacgccctcc   1320
tcacctacct ggagcaggtg cgcatgggca ttgcaggagt ggtgagggac aaggacacgg   1380
agcttgggat tgctgacgct gtcattgccg tggatgggat taaccatgac gtgaccacgg   1440
cgtggggcgg ggattattgg cgtctgctga ccccagggga ctacatggtg actgccagtg   1500
ccgagggcta ccattcagtg acacggaact gtcgggtcac ctttgaagag ggccccttcc   1560
cctgcaattt cgtgctcacc aagactccca aacagagctg cgcgagctgc tggcagctgg   1620
ggccaaggtg cccccggacc ttcgcaggcg cctggagcgg ctaaggggac agaaggattg   1680
atactgcggt ttaagagccc tagggcaggc tggacctgtc aagacgggaa ggggaagagt   1740
agagagggag ggacaaagtg aggaaaaggt gctcattaaa gctaccgggc accttaaaaa   1800
aaaaaaaaaa n                                                        1811
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 95
<211> LENGTH: 65
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  95
gaaaagggcg ccgngaggtg tccagtgcgg naangcgagc gatnccggag aaccggnggg     60
agncn                                                                 65
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 96
<211> LENGTH: 537
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  96
ncgcgtccgg gaagcacgtc cagcctgcca gctatgagca aagtccggcg gctacactat     60
gaggggctaa tttttaggtt caagttcctc atgcttatca ccttggcctg cgctgccatg    120
actgtcatct tcttcatcgt tagtcagcta ggatgcgtga cagcctagcc tcccctcctt    180
aatcacatac agaagagttc tctgtgttat gacagcaggt aacggaaggc cattggaaat    240
ggggcggcgt cacagtccaa gtgaacagtg cctttttcac aggcatctat gggatgtgga    300
atctgtatgt ctttgctctg atgttcttgt atgcaccatc ccataaaaac tatggagaag    360
accagtccaa tggcgatctg ggtgtccata gtggggaaga actccagctc accaccacta    420
tcacccatgt ggacggaccc actgagatct acaagttgac ccgcaaggag gcccaggagt    480
aggaggctgc agcgcccggc tgggacggtc tctccatacc ccagcccctc taactag       537
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 97
<211> LENGTH: 179
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  97
gtccgcntgc cgccganggt cccacgcggn aacgctggga ggangcaggc agggtagcaa     60
agcggcggcg ggcgcggcag ctctgtggca cctgtagggg tttactntnc nggccactta    120
agggacaact tttgtccaag caaggccaac tgcattttat tacacgccca ctgcgtgca     179
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 98
<211> LENGTH: 514
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  98
gatcgacccc cgtccggtga tttaatcgct atagctaaaa tacgtcaaat atacgttgtc     60
atgtgcttga acatgatgct aaccctgaca ggatgaagga aagtaatatt ctttcagtgt    120
agttcaggag agcatttgtt ttcttttcta ccaattaacc catcattgct tttaaacaac    180
catctgaagg agcaganagg cagggtagaa gacagaaggg ggatctatgt ggtaactaaa    240
gaatgtttct gttttgttaa ttattgtgtg tgtgtggttt tattgtttgc ttaacagaat    300
caaaaactga aaaaaatgag aatacccggg aaatgngcgt ctctgtttat gacttcttgc    360
tgatgttcta cacctgtgtt aaatgctcta ctgtctttgt ttcaacagac atttgttcac    420
tgcccagctc gttttgtgtc ctgagcccta tgcccagccc accttataaa tcatgcctgt    480
ttagatgttt gattttgttc tgtttgctat tgtt                                514
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 99
<211> LENGTH: 616
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine  proteases
<400> SEQUENCE:  99
tttttacccc tggggattta ttaatcatgc ggtttaattc caattaaatg gactccttgg     60
gagaaaagga ttggattgat gggggggttc ccaatttaat ccatggtacg gcgaattaaa    120
gggcattcct aaatggtggt tattcagtta aaattaattg gcacctttgt ggtaacacat    180
gggaactcct ggttttcaca gtttttcccc caacttatca cagccccgac aatagttcca    240
tttgtggcat ccatacagac taagggggcc tcagagtctc ccttacaggc atcgatggga    300
ccatcatatg tacccgcgca ttccattttc ttttcataga aacggatttc gtaaaactta    360
gagcagttgc ttattagttt tacttcaccc cactgcaagt gaaagactct ttcgctatct    420
atttctcgtc cccagccaga aacgatgcat gtatcatagg gttggatagg gtatggagac    480
aatgggacac aggcggggat ggaacgaggc aagtcacaat ctctttttgg tgtccggctt    540
tttttccatt tcattcaagg cggatgtcca tttggggaag tggcctgcca tgttggtttt    600
cttggaaaat aaatct                                                    616
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 100
<211> LENGTH: 220
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  100
gcttcaactg gctcctctcc tgtttctccc ttgtgggggc cgcctttggc tgcggggtcc     60
ccgccatcca ccctgtgctc agcggcctgt ccangatcgt gaatggggag gacgccgtcc    120
ccggctcctg gccctggcac gtgtccctgc aggacaaaac cggctcccac ttctgcgggg    180
gctccctcat cagcgatgac tgggtggtca ccgctgccca                          220
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 101
<211> LENGTH: 1856
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  101
cgtccggttc tagatcgcga gcggccgccc tttttttttt ttttttttga aataaaacta     60
taatataaat tctcctatta aataaaatta ttttaagttt tagtgtcaaa agtgagatgc    120
tgagagtagg tgataatgta tattttacag agtgggggtt ggcaggatgg tgacattgaa    180
catgattgct ctctgtctct tttttcagct tatgggtatt tatcttctat tagtatttgt    240
atcttcagtt cattccactt taggaaacag agctgccaat tgaaacagaa gaagaaaaaa    300
aaaaaagcag cagacaacac actgtagagt cttgcacaca cacaagtgcc caggcaaggt    360
gcttggcaga accgcagagt gggaagagag tactggcatc gggtttcctt gggatcaatt    420
tcattaccgt gtacctttcc cattgtggtc atgccatttg gcagggggag aatgggaggc    480
ttggccttct ttgtgaggca gtgtgagcag aagaagctga tgccagcatg tcactggttt    540
tgaagggatg agcccagact tgatgttttg ggattgtcct tattttaacc tcaaggtctc    600
gcatggtggg gcccctgacc aacctacaca agttccctcc cacaagttgg acatcaagtg    660
tcttctctgt gaggcatcct ggccattccc actcccctgg tgttggtcca gcctctcctc    720
cacacaaaga aagaacttgg gtgaaggctg agtgtgaggc acctgaagtt tccctgcgga    780
gtcgataaat tagcagaacc acatccccat ctgttaggcc ttggtgagga ggccctgggc    840
aaagaagggt ctttcgcaaa gcgatgtcag agggcggttt tgagctttct ataagctata    900
gctttgttta tttcacccgt tcacttactg tataatttaa aatcatttat gtagctgaga    960
cacttctgta tttcaatcat atcatgaaca ttttattttg ctaaatcttg tgtcatgtgt   1020
aggctgtaat atgtgtacat tgtgtttaaa agaaaaatga aacccacatg ccgccatttt   1080
cctgaatcaa attctgcagt ggaatggaga ggaaaatact tctaggcaag cagctagact   1140
ggtgaattgg gggaaataga aggaactagt aactgagact cctccagcct cctccctatt   1200
ggaatcccaa tggctcctgg agtaggaaaa aagtttaaac tacattcatg ttcttgttct   1260
gtgtcacttg gccctgggta gtctaccatt tacttcaccc caagtcctgc tgcccatcca   1320
gttgggaagc catgattttc ctaagaatcc agggccatgg gagatacaat tccaagttct   1380
cgcttcctcc tttgggcatc tcttctgcct cccaatcaag gaagctccac gctcaggctc   1440
tcagctctcg ggccagtgct ctgctctgtc cagggtaggt aatactggga gactcctgtc   1500
ttttaccctc ccctcgttcc agacctgcct catggtggca acatggttct tgaacaatta   1560
aagaaacaaa tgactttttg gaatagccct gtctagggca aactgtggcc cccaggagac   1620
actacccttc catgccccag acctctgtct tgcatgtgac aattgacaat ctggactacc   1680
ccaagatggc acccaaagtg ttttggcttc tggctaccta aggttaacat gtcactagag   1740
tatttttatg aagagacaaa cattataaaa atctgatggc aaaagcaaaa caaaatggaa   1800
agtaggggag gtggatgtga caacaacttc caaattggct ctttggaggc gagggg       1856
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 102
<211> LENGTH: 161
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  102
tcctgattct cccttgtngg ggccncctat ggctgcgggg tccccgccat ccaccctgtg     60
ctcaacggtc tgtccaagat cgtgantngg gaggacnccg tccccngctc ctgnccctgt    120
cnggtgtccc tgcatganaa naccggnttc cacttctgcg g                        161
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 103
<211> LENGTH: 371
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  103
gaaaagctat cttctcngcc tcaatcttnt aggactgcat gcaagatgga agcacgcaca     60
gcacggttcc tctctccnct gcattgtttc actgggctca cctgcttctg aaaacggctc    120
cctgtcttgg gctctaatga ggatctgggg ttgggagagg ctgttggtct gagggcagta    180
atcacangct gcaggctaga gggggcagtt atgactgcct gaaagtgggt gagggattgc    240
acttcagaaa aacatctaaa aaacttagtc tatgtttgaa ttccccacct ccatcccatc    300
tatgggaaga ccgttcagtg tttanagaat ggggagatgg gtccctgcac ttggcctctc    360
cataagcctt g                                                         371
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 104
<211> LENGTH: 2886
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  104
gctggcgaag ctgaaacccg agctcccgct cagctggggc tcggggaggt ccctgtaaaa     60
cccgcctgcc cccggcctcc ctgggtccct cctctccctc cccagtagac gctcgggcac    120
cagccgcggc aaggatggag ctgggttgct ggacgcacgt tggggctcac ttttcttcag    180
ctccttctca tctcgtcctt gccaagagag tacacagtca ttaatgaagc ctgccctgga    240
gcagagtgga atatcatgtg tcgggagtgc tgtgaatatg atcagattga gtgccgtctg    300
ccccggaaag agggaagtcg tgggttatac catcccttgc tgcaggaatg aggagaatga    360
gtgtgactcc tgcctgatcc acccaggttg taccatcttt gaaaactgca agagctgccg    420
aaatggctca tggggggggt taccttggat gactttctat gttgaagggg ttctacttgt    480
gcagagtgcc gagcaggctg gtacggaang gagactgcat gccgatgttg gccaggttct    540
gccgaacccc aaagggtcag attttgtttg gaaagctatc cccttaaatg ctcacttgtg    600
aatggaccat tcatgctaaa cctgggtttg tcatccaact aagatttgtc atgttgagcc    660
tggagtttga ctacatgtgc cagtatgact atgttgaggt tcgtgatgga gacaacccgc    720
gatggccaga tcatcaagcg tgtctgtggc aacgagcggc cagctcctat ccagagcata    780
ggatcctcca ctcccacgtc cctcttccac tccggatggc tccaagaatt ttgacggttt    840
ccatgccatt tatgaggaga tcacagcatg ctcctcatcc ccttgtttcc atgacggcac    900
gtgcgtcctt gacaaggctg gatcttacaa gtgtgcctgc ttggcaggct tatactgggc    960
agcgctgtga aaatctcctt gaagaaagaa actgctcaga ccctgggggc ccagtcaatg   1020
ggtaccagaa aataacaggg ggccctgggc ttatcaacgg acgccatgct aaaattggca   1080
ccgtggtgtc tttcttttgt aacaactcct atgttcttag tggcaatgag aaaagaactt   1140
gccagcagaa tggagagtgg tcagggaaac agcccatctg cataaaagcc tgccgagaac   1200
caaagatttc agacctggtg agaaggagag ttcttccgat gcaggttcag tcaagggaga   1260
cacccaattc accagctata ctcagcggcc ttcagcaagc agaaacttgc aagagtgccc   1320
ctaccaagaa gccagccctt ccctttggag atcttgccca tgggatacca acatcttgca   1380
tacccagctc cagtatgagt gcatctcacc cttctaccgc cgcctgggca gcagcacgga   1440
ggacatgttt gaggactggg aagtggagtg ggcggggcac catcctgcat ccctatctgc   1500
gggaaaattg agaacatcac tgctccaaag acccaagggt tgcgctggcc gtggcaggca   1560
gccatctaca ggaggaccag cggggtgcat gacggcagcc tacacaaggg agcgtggttc   1620
ctagtctgca gccggtgccc tggtgaatga gcgcacttgt ggtggtggct gcccactgtg   1680
ttactgacct ggggaaggtc accatgatca agacagcaga cctgaaagtt gttttgggga   1740
aattctaccg ggatgatgac cggggatgag aagaccatcc agagcctaca gatttctgct   1800
atcattctgc atcccaacta tgaccccatc ctgcttgatg ctgacatcgc catcctgaag   1860
ctcctagaca aggcccgtat cagcacccga gtccagccca tctgcctcgc tgccagtcgg   1920
gatctcagca cttccttcca ggagtcccac atcgactgtg gctggctgga atgtcctggc   1980
agacgtgagg agccctggct tcaagaacga cacactgcgc tctggggtgg tcagtgtggt   2040
ggactcgctg ctgtgtgagg aagcaacatg agggaccatg gcatcccagt ggagtgtcac   2100
tgataacatg ttctgtgcca gctgggaacc cactgcccct tctgatatct gcactgcaga   2160
gacaggaggc atcgcggctg tgtcctttcc gggacgagca tctcctgagc cacgctggca   2220
tttgatggga actggtcaag ctggagctta tgataaaaca tgcagccaca ggctctccac   2280
tgccttcacc aaggtgctgc cttttaaaag actggattga aagaaatatg aaatgaacca   2340
tgctcatgca ctccttgaga aagtgtttct gtatatccgt ctgtacgtgt gtcattgcgt   2400
gaagcagtgt gggcctgaag tgtgatttgg cctgtgaact tggctgtgcc agggcttctg   2460
acttcaggga caaaactcag tgaagggtga gtagacctcc attgctggta ggctgatgcc   2520
acgtccacta ctaggacagc caattggaag atgccagggc ttgcaagaag taagtttcgt   2580
tcaaagaaga ccatatacaa aacctctcca ctccactgac ctggtggtct tccccaactt   2640
tcagttatac gaatgccatc agcttgacca gggaagatct gggcttcatg aggccccttt   2700
tgaggctctc aagttctaga gacgctgcct gtgggacagc ccagggcagc agagctggga   2760
attgtggtgc atgcctttgt gtacatggcc acagtacaag tctggtcctt ttccttcccc   2820
atctcttgta cacattttaa taaaataaag ggttggcttc tgactacaaa aaaaaaaaaa   2880
aaaagg                                                              2886
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 105
<211> LENGTH: 407
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  105
cccgcgtccg tttttttttt tttttttttt tcaagggttc tgcatctcgt ttattacgca     60
cagaaataac aggtttagag tatattacaa aaagagctca aactgttcag atacagcaac    120
tgggcttact aggggacaga aggggaaata cgtcagacta ctgtacaggg acacaaagac    180
tcngtcatcc taaacaaagt attaaggtac atagacaagt ttnttgtaag acagaaaaca    240
gagaaatcca cagtaactnt aacacatccc ttaaggaata agcatgtatt tgtaggaagc    300
aaacaaagct ttccatagag aaaccacttt cacaggatga ttaggtggac ctgcaatgaa    360
gaaaatacat ttcaaaagat gggttcagac attacaccaa gttttca                  407
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 106
<211> LENGTH: 549
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  106
aacccacgcg tccgnttgct gggtgggaag atgtgtgtgg cagccgggag gcacacgggc     60
tggatgtgcc ggccgaaagg cagagggctg gtcagctcct gcacagccac gtcaaagtcg    120
gccgtgtccg cgttgtacag ggggtgcttg acgatctgga ccacctgggc ccgcacggtg    180
ctggcctccg agccgctgag gtaggtcgca cccacgtagg ccacccactt cgtcgggtct    240
tggaacctgc aggagcaaac cccagctcag aagccaccga gggtcagagc cgtcggggga    300
ggcagacggg acactcgcct tgggtgcaaa atgtaagggg tatcccccca cattaatatt    360
tatgaatagt atttataaaa atcaggccag acacagtggc tcatgcctgt aatcccacac    420
ttttggaggc tgaagcggna ggatcacctg agcccaggag ttaagaacga tcctgggcaa    480
catagcgaaa cacagtcttt aaaaacaaca acaaaaaaca ggccaggtgc ggtggctcat    540
gcctgtaat                                                            549
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 107
<211> LENGTH: 796
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  107
ggagtcgacc acgcgtccgg tgcaaagagg acagcacatg catctcactg cccaaggtct     60
gtgatgggca gcctgattgt ctcaacggca gcgacgaaga gcagtgccag gaaggggtgc    120
catgtgggac attcaccttc cagtgtgagg accggagctg cgtgaagaag cccaacccgc    180
agtgtgatgg gcggcccgac tgcagggacg gctcggatga ggagcactgt gactgtggcc    240
tccagggccc ctccagccgc attgttggtg gagctgtgtc ctccgagggt gagtggccat    300
ggcaggccag cctccaggtt cggggtcgac acatctgtgg gggggccctc atcgctgacc    360
gctgggtgat aacagctgcc cactgcttcc aggaggacag catggcctcc acggtgctgt    420
ggaccgtgtt cctgggcaag gtgtggcaga actcgcgctg gcctggagag gtgtccttca    480
aggtgagccg cctgctcctg cacccgtacc acgaagagga cagccatgac tacgacgtgg    540
cgctgctgca gctcgaccac ccggtggtgc gctcggccgc cgtgcgcccc gtctgcctgc    600
ccgcgcgctc ccacttcttc gagcccggcc tgcactgctg gattacgggc tggggcgcct    660
tgcgcgaggg cggccccatc agcaacgctc tgcagaaagt ggatgtgcan ttgatcccac    720
aggacctgtg cagcgaggtc tatcgctacc aggtgacgcc acgcatgctt gtgtgccggc    780
taccgcaagg gcaagn                                                    796
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 108
<211> LENGTH: 1828
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  108
gacgcgtggg tcaacatcca aaactacaac cacgatatag ctctggtgca gctgcaggag     60
cctgtgcccc tgggacccca cgttatgcct gtctgcctgc caaggcttga gcctgaaggc    120
ccggcccccc acatgctggg cctggtggcc ggctggggca tctccaatcc caatgtgaca    180
gtggatgaga tcatcagcag tggcacacgg accttgtcag atgtcctgca gtatgtcaag    240
ttacccgtgg tgcctcacgc tgagtgcaaa actagctatg agtcccgctc gggcaattac    300
agcgtcacgg agaacatgtt ctgtgctggc tactacgagg gcggcaaaga cacgtgcctt    360
ggagatagcg gtggggcctt tgtcatcttt gatgacttga gccagcgctg ggtggtgcaa    420
ggcctggtgt cctggggggg acctgaagaa tgcggcagca agcaggtcta tggagtctac    480
acaaaggtct ccaattacgt ggactgggtg tgggagcaga tgggcttacc acaaagtgtt    540
gtggagcccc aggtggaacg gtgagctgac ttacttcctc ggggcctgcc tcccctgagc    600
gaagctacac cgcacttccg acagcacact ccacattact tatcagacca tatggaatgg    660
aacacactga cctagcggtg gcttctccta ccgagacagc ccccaggacc ctgaaaggca    720
gagtgtggta tagggaaaag gctccaggca ggagacctgt gttcctgagc ttgtccaagt    780
ctctttccct gtctgggcct cactctaccg agtaatacaa tgcaggagct caaccaaggc    840
ctctgtgcca atcccagcac tcctttccag gccatgcttc ttaccccagt ggcctttatt    900
cactcctgac cacttatcaa acccatcggg tcctactgtt ggtataactg agcttggacc    960
tgactattag aaaatggttt ctaacattga actgaatgct gcatctgtat attttcctgc   1020
tctgccttct gggactagcc ttggcctaat ccttcctcta ggagaagagc attcaggttt   1080
tgggagatgg ctcatagcca agcccctctc tcttagtgtg atcccttgga gcaccttcat   1140
gcctggggtt tctctcccaa aagcttcttg cagtctaagc cttatccctt atgttcccca   1200
ttaaaggaat ttcaaaagac atggagaaag ttgggaaggt ttgtgctgac tgctgggagc   1260
agaatagccg tgggaggccc accaagccct taaattccca ttgtcaactc agaacacatt   1320
tgggcccata tgccaccctg gaacaccagc tgacaccatg ggccgtccac acctgctgct   1380
ccagacaagc acaaagcaat ctttcagcct tgaaatgtat tatctgaaag gctacctgaa   1440
gcccaggcct gaatatgggg acttagtcga ttacctggaa aaagaaaaga cccacactgt   1500
gtcctgctgt gcttttgggc aggaaaatgg aagaaagagt ggggtgggca cattagaagt   1560
cacccaaatc ctgccaggct gcctggcatc cctggggcat gagctgggcg gagaatccac   1620
cccgcaggat gttcagaggg acccactcct tcatttttca gagtcaaagg aatcagaggc   1680
tcacccatgg caggcagtga aaagagccag gagtcctggg ttctagtccc tgctctgccc   1740
ccaactggct gtataacctt tgaaaaatca ttttctttgt ctgagtctct ggttctccgt   1800
cagcaacagg ctggcataag gtcccctn                                      1828
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 109
<211> LENGTH: 488
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  109
ccgtccgggc tcgggttgag gggctgggga cgtcctctgc tgactgtggc caccgccctg     60
atgctgcccg tgaagccccc cggctcctgg ggggcccaga tcatcggggg ccacgaggtg    120
accccccact ccaggcccta catggcatcc gtgcgcttcg ggggccaaca tcactgcgga    180
ggcttcctgc tgcgagcccg ctgggtggtc tcggccgccc actgcttcag ccacagagac    240
ctccgcactg gcctggtggt gctgggcgcc cacgtcctga gtactgcgga gcccacccag    300
caggtgtttg gcatcgatgc tctcaccacg caccccgact accaccccat gacccacgcc    360
aacgacatct gcctgctgcg gctgaacggc tctgctgtcc tgggccctgc agtggggctg    420
ctgaggctgc cagggagaag ggccaggccc cccacagcgg ggacacggtg ccgggtggct    480
ggctgggc                                                             488
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 110
<211> LENGTH: 1872
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  110
tggatcgccc ccgcgtccgg catgatttaa gattaaattc atgtattgaa aatattgttc     60
agaccccatg tgacataact ggagccagtg cagtgccatg aagaactacg agattagcct    120
ggatattaac ttgtcttcta gagaatagat ttcatgttcc attcttctgc aatggttaat    180
tcacacagaa aaccaatgtt taacattcac agaggatttt actgcttaac agccatcttg    240
ccccaaatat gcatttgttc tcagttctca gtgccatcta gttatcactt cactgaggat    300
cctggggctt tcccagtagc cactaatggg gaacgatttc cttggcagga gctaaggctc    360
cccagtgtgg tcattcctct ccattatgac ctctttgtcc accccaatct cacctctctg    420
gactttgttg catctgagaa gatccgaagt cttggtcagc aatgctaccc agtttatcat    480
cttgcacagc aaagatcttg aaatcacgaa tgccaccctt tcagtcagag gaagattcaa    540
gatacatgaa accaggaaaa gaactgaaag ttttgagtta ccctgctcat gaacaaattg    600
cactgctggt tccagagaaa cttacgcctc acctgaaata ctatgtggct atggacttcc    660
aagccaagtt aggtgatggc tttgaagggt tttataaaag cacatacaga actcttggtg    720
gtgaaacaag aattcttgca gtaacagatt ttgagccaac ccaggcacgc atggctttcc    780
cttgctttga tgaaccgttg ttcaaagcca acttttcaat caagatacga agagagagca    840
ggcatattgc actatccaac atgccaaagg ttaagacaat tgaacttgaa ggaggtcttt    900
tggaagatca ctttgaaact actgtaaaaa tgagtacata ccttgtagcc tacatagttt    960
gtgatttcca ctctctgagt ggcttcactt catcaggggt caaggtgtcc atctatgcat   1020
ccccagacaa acggaatcaa acacattatg ctttgcaggc atcactgaag ctacttgatt   1080
tttatgaaaa gtactttgat atctactatc cactctccaa actggattta attgctattc   1140
ctgactttgc acctggagcc atggaaaatt ggggcctcat tacatatagg gagacgtcac   1200
tgctttttga ccccaagacc tcttctgctt ccgataaact gtgggtcacc agagtcatag   1260
cccatgaact ggcgcaccag tggtttggca acctggtcac aatggaatgg tggaatgata   1320
tttggcttaa ggagggtttt gcaaaataca tggaacttat cgctgttaat gctacatatc   1380
cagagctgca atttgatgac tattttttga atgtgtgttt tgaagtaatt acaaaagatt   1440
cattgaattc atcccgccct atctccaaac cagcggaaac cccgactcaa atacaggaaa   1500
tgtttgatga agtttcctat aacaagggag cttgtatttt gaatatgctc aaggattttc   1560
tgggtgagga gaaattccag aaaggaataa ttcagtactt aaagaagttc agctatagaa   1620
atgctaagaa tgatgacttg tggagcagtc tgtcaaatag ttgtttagaa agtgatttta   1680
catctggtgg agtttgtcat tcggatccca agatgacaag taacatgctc gcctttctgg   1740
gggaaaatgc agaggtcaaa gagatgatga ctacatggac tctccagaaa ggaatccccc   1800
tgctggtggt taaacaagac gggtgttcac tccgactgca acaggagcgc ttnctncagg   1860
gggttttcca gn                                                       1872
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 111
<211> LENGTH: 606
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  111
cgtccggggc agtgcaggaa cacctccttc tttgaaactg aaggctgtgg gaagaagtgc     60
aatggccatg gggtctgtaa caacaaccag aactgccact gcctgccggg ctgggccccg    120
cccttctgca acacaccggg ccacgggggc agtatcgaca gtgggcctat gccccctgag    180
agtgtgggtc ctgtggtagc tggagtgttg gtggccatct tggtgctggc ggtcctcatg    240
ctgatgtact actgctgcag acagaacaac aaactaggcc aactcaagcc ctcagctctc    300
ccttccaagc tgaggcaaca gttcagttgt cccttcaggg tttctcagaa cagcgggact    360
ggtcatgcca acccaacttt caagctgcag acgccccagg gcaagcgaaa ggtgatcaac    420
actccggaaa tcctgcggaa gccctcccag cttctncccg gccccctcag attatctgcg    480
tggtgggtcc cacctgcacc actgccagct nacctgacag ggctgctagg aacttcccan    540
ggccgggtct caaatagaga ngacgggtcg tccaagaagc ctctcaagcc ggcaattncc    600
cccccc                                                               606
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 112
<211> LENGTH: 153
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  112
ggagattttc ncatcatcct gaacccatct gcctccttcc catcctanaa agcagctgtg     60
acaacattca gggcttcatc gangagttcc ttnacatctt cagctccttg ctgcaggaga    120
agaggttcct ccgggactat gatgcactct tcc                                 153
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 113
<211> LENGTH: 512
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  113
cgaaatccac atggtccgaa accttncctg caantttttc agggnatana tggaagatat     60
taaataccag gtatgganaa ccnttgttta tgatttccaa actcatcant ggtgtcacag    120
aatttcttaa tactganggt gaactcnaag agctcaagaa cttcatgaaa aactatgatg    180
gggtagctgc tgcttctttc tcacganctg tggaaactgt cnaagccaat gtgcgctgga    240
aaatgcttta ccaagacgag cttttccaat ggttaggaaa agctctaaga cactaatata    300
tgtatcttat aaacaancna ttcanctcag aagtttatga gaagacacgc tttttgtgga    360
atgagganta tgtnctacct anaaaanggc cagattttca gtgttaacnt gtgggaggaa    420
ttttttttnt agttcntanc ttttggtttt gggggatatt ttttatttgt ttcattcatt    480
cctgttctgt ttctctactg ggtgttcctc tc                                  512
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 114
<211> LENGTH: 789
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  114
aagggcaagg accgggtcta agatgttgac ccaggantga gccaacgtgt tctctggaag     60
aggaggagag gggctaagag gaggctggag acagtctctg cccttatcgg acctctagta    120
acggccgcca gtgtgctnta aagccaggag gtgggcaggg atgggccccc tcaggtcgat    180
gagctcgggc ccatagtggc ggtggagggc cctgcgcacg taggtgtgcg ggttcaggta    240
gagtggccgc agctcctgga atagccgctc caggtcttgc tccagggtat ccgactcata    300
cttggagtgc cacaaggccc ccatgtcttt gtaacctagg acaggagaga ggactcacca    360
ggagctcacc atctcaccct ttagccatgg cctagctgac aggataccca gacgccttct    420
agggaagcca ctcaacctcg ctgaccgtct gggtcttctt tggcaaaacg gggagaatac    480
ctgcccattt cagaaaggca ctgagcaaag tccatgatcc gagctcccca ccatgcctgc    540
aaggcctgag tcccctctta tcccacctca tccttagccc tgtggccacc tgggcttctt    600
tcaggtcttc cagagcaccg gctctcctgc cgcggagctc tgcctaggct gctctttttn    660
acatttgctt ccgtcttttg ccatctttca ggtcttggat aaatgtcaga gtcttccctg    720
tcattgttgc agcagctctt ctcatttctt tctcagaagc tcttctatcc gcananccag    780
atggtagtn                                                            789
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 115
<211> LENGTH: 617
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  115
ttaaattgcc aagtgatttt acttcaagat gacatcagaa ttgctaaaag gtgatgtaac     60
cgtcagagtg actattgatt ataactccca gtaagtgtca acgtgatttt ctccattgtg    120
tgggcttcca ttagtattta ctcattaggt tcagtagttt tcattatttt ctcttccata    180
aattctattg cttgtgaaaa gccaccaaag agaagtgaaa ccagaaaaag gatgcaacga    240
gtaaatatta aaagtagtgc tcagtttata ttcgcaagtg tgctggctgt aatacgatat    300
tgtttgtcag gtggagggcc actatctata ctacctcctt ttcctctcag ttcacatgtt    360
ggtggttgcc acccatgcag acagtgacaa tgttttttgt tgttacatac tcctttgtaa    420
ttgcatgttt taagatcaca ctcaaaatgc aggtcttgat aagaagtaca attgtgttta    480
agacagtagc tccctgggcc acaggtttgc accatccact accagcccca tttctgggaa    540
gtctgtcccc tggtgttgct tcatagccaa agcatttttc ttcttttatg tcgtgtacta    600
atatattacg aaatgtn                                                   617
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 116
<211> LENGTH: 756
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  116
acgcccgtct ggtttttttt gtttgtttnn cngagggttt tctttgcatg agagttgtat     60
gtaaccagtg atatgattat tcctgaatgt acagacagaa gtaagcctgg acattgttaa    120
atagtccctg ctttaaggga ctacgataat gtgtactatg acaaacgtgc tttattcttc    180
taacgcagta agaattaggt ggaatttttt ccttcaacca agtgcaggaa agccctgtgt    240
gtcttggttt agttatggtt tcatttctag ccatacaatt gatgaattgt gtacaacttt    300
tgttagtacc aaaataatct gttatatgaa cagacttcta aaataacgtc tgtatatttt    360
atatatagat acatatatga aagaaggctt ttattgaaca gcttatcttc cacttgcagg    420
tttatggaaa cagcagtatt tgaaaataaa taaaaagttg ggagaattcc ttgctgttag    480
aaagaatgtg gccattattt tgattttttg aatgagatat ataatccaaa gtactgctga    540
acttgtgagt tgcagttatt cctaaacatt tcagctagga gaataccact tgattttaga    600
aaaccaaact gtttgtctct ggtttccttg aatttaaatg tttgggatta cctgttttaa    660
tctgtccttg gggantttaa aaataattct gtaatgtnng ttgcaatatn tcntgcnccc    720
ccccgaattt gggttccctg gttcccgaat tcccnn                              756
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 117
<211> LENGTH: 667
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  117
ttaaagggag ttttctggga aaaggaacct ttaatattgc ttaagacact gtagagtaag     60
taagaatagg ctaggaatcc tttgctgtga tagctaatgc ttgcaatcct gacatgaaat    120
gtccatgaag ttttatttaa acagtgagac atggcttcat atttttctat taaaaaattg    180
gatattaaaa atgaagtata aagtttagtc tccttctttt tcccatttct cttatccttc    240
ttcatcttct ttactttttg tgcgtttctt aaaaagcaca tgtaagcaaa ataataaaaa    300
agcaaccaaa ggaagaaggc acaatagtga caggtaacgc aactttccca tcacatttaa    360
tccttccatg ttgttcttag gaggtgggcc actatcagca ctacctccat agcctttgtc    420
cttgcagtat gggggtgcca ttcatggttg cagtgacagt gttgtttgtt gttgcagatt    480
cccctcatgt tgcaggtctt aggctgacag gcttgtgaca agatgaacca tactggcaca    540
cttcttacgg atgcagatct tttctggacc acatactggg ccatctttca cctcaccaat    600
atcaggtata gccatcccta aatgataatc agtgccccag caggtggcac ccttgatatg    660
agtgtgn                                                              667
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 118
<211> LENGTH: 127
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  118
ggatcatttc agattggaga acaaggagtn gattgcctga acacctgaac atccgtttat     60
gggggccaga tagaatttgt tttcanatan gcttaacagg cntcattaaa atttcattct    120
gtgtgtt                                                              127
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 119
<211> LENGTH: 400
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  119
ggtgttcacc tacgagaagg gctactgctt cgtgtactac ctgtcccagc tctgcggaga     60
cccacagcgc tttgatgact ttctccgagc ctatgtggag aagtacaagt tcaccagcgt    120
ggtggcccag gacctgctgg actccttcct gagcttcttc ccggagctga aggagcagag    180
cgtggactgc cgggcaggcc gccggctggc tgagccggac cttgttcagg gagtcagcct    240
gacccggccc gtggaggccc ttttccagct gtggaccgca gaacctctgg accacggcag    300
ctgcctcggc agcgccattg acatctccaa gtggaggacc ttccagacag cactcttcct    360
ggaccggctc ctggatgggt ccccgctgcc gcaggaggtn                          400
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 120
<211> LENGTH: 1366
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  120
cacgagcgcg tgtgggccga gccatgcctc ctgcccacgg ccaccagcaa gctgtcgggc     60
gcagtggagc agtggctgag tgcagctgag cggctgtatg ggccctacat gtggggcagg    120
tacgacattg tcttcctgcc accctccttc cccatcgtgg ccatggagaa cccctgcctc    180
accttcatca tctcctccat cctggagagc gatgagttcc tggtcatcga tgtcatccac    240
gaggtggccc acagttggtt cggcaacgct gtcaccaacg ccacgtggga agagatgtgg    300
ctgagcgagg gcctggccac ctatggaccn cgcgtccgca ccaccgagac ctacggtgct    360
gccttcacct gcctggagac tgccttccgc ctggacgccc tgcaccggcn gatgaagctn    420
ctgggagagg acagcccggt cagcaaactg caggtcaagc tggagccagg agtgaatccc    480
agccacctga tgaacctgtt cacctacgag aagggctact gcttcgtgta ctacctgtcc    540
cagctctgcg gagacccaca gcgctttgat gactttctcc gagcctatgt ggagaagtac    600
aagttcacca gccgtggtgg cccaggacct gctggactcc ttcctgagct tcttcccgga    660
gctgaaggag cagagcgtgg actgccgggc agggctggaa ttcgagcgct ggctcaatgc    720
cacaggcccg ccgctggctg agccggacct gtctcagggg atccagcctg acccggcccg    780
tggaggccct tttccagctg tggaccgcag aacctctgga ccaggcagct gcctcggcca    840
gcgccattga catctccaag tggaggacct tccagacagc actcttcctg gaccggctcc    900
tggatgggtc cccgctgccg aaggaggtgg tgatgagcct gtccaagtgc tactcctccc    960
tgctggactc gatgaacgct gagatccgca tccgctggct gcagattgtg gtccgcaacg   1020
actactatcc tgacctccac agggtgcggc gcttcctgga gagccagatg tcacgcatgt   1080
acaccatccc gctgtacgag gacctctgca ccggtgccct caagtccttc gcgctggagg   1140
tcttctacca gacgcagggc cggctgcacc ccaacctgcg cagagccatc cagcagatcc   1200
tgtcccaggg cctggggttc cagcacagag cccggcctta ggagcccagc acgggagctt   1260
ggnaaagggt tgaaggcagg acacaggatt ngggacgcac agggccttgt tngttttggg   1320
ggacgagggn ccccagcagt tgccnttttt tttnaggggg acgttn                  1366
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 121
<211> LENGTH: 606
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: neprilysin family of proteases
<400> SEQUENCE:  121
gtcggctacc cggacttcct gctgaaaccc gatgctgtgg acaaggagta tgagtttgag     60
gtccatgaga agacctactt caagaacatc ttgaacagca tccgcttcag catccagctc    120
tcagttaaga agattcggca ggaggtggac aagtccacgt ggctgctccc cccacaggcg    180
ctcaatgcct actatctacc caacaagaac cagatggtgt tccccgccgg gatcctgcag    240
cccaccctgt acgaccctga cttcccacag tctctcaact acgggggcat cggcaccatc    300
attggacatg agctgaccca cggctacgac ggactggggg ggccagtatg accgctcagg    360
gaacctgctt gcactggtgg gacggaggct tccttacagc cgntttcctg cgaaaggctg    420
agtgcatcgt tccctntttt atggacaact ttcaatgtnt tacaaccagg cggtgaacgg    480
gaaacacang tttgggagaa catcgcagta tggggcggnc ttaagttggc ttaccacgct    540
attagagttg gttncgggan ggccccagga gcaccatttc ccggttaaat acanactgaa    600
ccagtn                                                               606
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 122
<211> LENGTH: 1507
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  122
cgctgcgccc tcacctgggc ccttcttgcc tttctggtcc caggagtgcc gcgacctctg     60
ctgctttgct cacaactgct cgctgcgccc gggggcccag tgcgcccacg gggactgctg    120
cgtgcgctgc ctgctgaagc cggctggagc gctgtgccgc caggccatgg gtgactgtga    180
cctccctgag ttttgcacgg gcacctcctc ccactgtccc ccagacgttt acctactgga    240
cggctcaccc tgtgctgctg gcattggcta ctgccgcgat gccctagggc ccccgttgcg    300
cccacggggc ctgctgcgtg cgctgcctgg ctcccaccca gctcccgagg cctgtttcca    360
ggtggtgaac tctgcgggag atgctcatgg aaactgcggc caggacagcg agggccactt    420
cctgccctgt gcagggaggg atgccctgtg tgggaagctg cagtgccagg gtggaaagcc    480
cagcctgctc gcaccgcaca tggtgccagt ggactctacc gttcacctag atggccagga    540
agtgacttgt cggggagcct tggcactccc cagtgcccag ctggacctgc ttggcctggg    600
cctggtagag ccaggcaccc agtgtggacc tagaatggtg tgccagagca ggcgctgcag    660
gaagaatgcc ttccaggagc ttcagcgctg cctgactgcc tgccacagcc acggggtttg    720
caatagcaac cataactgcc actgtgctcc aggctgggct ccacccttct gtgacaagcc    780
aggctttggt ggcagcatgg acagtggccc tgtgcaggct gaaaaccatg acaccttcct    840
gctggccatg ctcctcagcg tcctgctgcc tctgctccca ggggccggcc tggcctggtg    900
ttgctaccga ctcccaggag cccatctgca gcgatgcagc tggggctgca gaagggaccc    960
tgcgtgcagt ggccccaaag atggcccaca cagggaccac cccctgggcg gcgttcaccc   1020
catggagttg ggccccacag ccactggaca gccctggccc ctggaccctg agaactctca   1080
tgagcccagc agccaccctg agaagcctct gccagcagtc tcgcctgacc cccaagcaga   1140
tcaagtccag atgccaagat cctgcctctg gtgagaggta gctcctaaaa tgaacagatt   1200
taaagacagg tggccactga cagccactcc aggaacttga actgcagggg cagagccagt   1260
gaatcaccgg acctccagca cctgcaggca gcttggaagt ttcttccccg agtggagctt   1320
cgacccaccc actccaggaa cccagagcca cattagaagt tcctgagggc tggagaacac   1380
tgctgggcac actcttccag ctcaataaac catcagtccc agaaagcaaa ggtcacacag   1440
cccctgacct ccctcaccag tggaggctgg ggtagtgctg gccatcccaa aagggctctg   1500
tcctggn                                                             1507
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 123
<211> LENGTH: 531
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  123
ccgcatgatt ctgttggttg ttattgtttt cgacgaacca actgtctcat gaccctgttc     60
ctgatcttaa tgatatgatg agcaattgtt cttatgagat aattcaacgc aagtttaatc    120
aatgggatcc ttgtttgagt gctccaaatg ttccatacac taattttcca tacgtagctc    180
ctcgttgtgg agacaagatc aaaaatcaga gggaagaatg tgactgtggc tcccttaaag    240
attgtgccag tgatagatgt tgtgagacct cttgtaccct ttctcttggc agtgtttgca    300
atacagcgac tttgctgcca taagtgtaaa tatgctgccc ctggagtggt ttgcagagac    360
ttgggtggta tatgtgatct accggaatac tgtgatggga aaaaggaaga gtgtccaaat    420
gacatctaca tccaggatgg aaccccatgt tcagcagtat ctgtttgtat aagaggaaac    480
tgcagtgacc gtgatatgca gtgtcaagcc ctttttggct accaagtgaa n             531
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 124
<211> LENGTH: 54
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  124
caaatccccc gtgccaggcg gccctaaata ttcctaaaaa aaaccncccc nccn           54
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 125
<211> LENGTH: 387
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  125
ttcttattcc aacaacaaaa gtgaattatg ggtttccctc atagaaaaag catacatgaa     60
agtcatggga ggatatgatt ttccaggatc caactccaat attgatcttc atgcactgac    120
tggcatggat accagaaaga attgctatgc attcagatag ccaaactttc agtaaggata    180
attctttcag aatgctttat caaagatttc acaaaggaga tgtcctcatc actgcgtcaa    240
ctggaatgat gacagaagct gaaggagaga agtggggtct ggttcccaca cacgcatatg    300
ctgttttgga tattagagag ttcaaggttt tgccttaaat cttttncttt natnnttctt    360
gttggataag acatttcagg gatccca                                        387
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 126
<211> LENGTH: 349
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  126
tccgtttcaa tttttattat gggaaaattt caaacatata caaaagtata gagaatagta     60
taatgaactc tcaaacatcc atcacacagc ttcagcaatt accaatttat ggccaatctt    120
gtttcatcta tgtactcaat taccccacac tcagatgatt ttgaagcgaa taccagtaac    180
atatcatttc acctgtacat ttttcagtat acttctctaa aagataatca ttttttaaaa    240
caacataacc acagtaccat atcacatctt aaaaaacaat aaatcaagaa gttatatttt    300
tatttcaaat tatgtaacaa ctggggacac aatcaataca tttcactgg                349
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 127
<211> LENGTH: 441
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  127
cacgcgtccg cccacgcgtc cggcagcggt atgcatctga gctcctgtcc cagctccagg     60
aaggggagtt ctgggtggag gaggaggagt tcctcaggga gtttgacgag ctcaccgttg    120
gctacccggt cacggaggcc ggccacctgc agagcctcta cacagagagg ctgctctgcc    180
atacgcgggc gctgcctggg gcctgggtca agggccagtc agcaggaggc tgccggaaca    240
acagcggctt tcccagcaac cccaaattct ggctgcgggt ctcagaaccg agtgaggtgt    300
acattgccgt cctgcagaga tccaggctgc acgcggcgga ctgggcaggc cgggcccggg    360
cactggtggg tgacagtcat acttcgtgga gcccagcgag catcccgggc aagcactacc    420
aggctgtggg tctgcacctc t                                              441
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 128
<211> LENGTH: 722
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  128
ctggcaccca tacctttaca ttagtggttt ctcaatatga aaaacagaac acaatccatt     60
acacggttcg ggtatattca gcatgcagct ttactttttc aaagattcct tcaccataca    120
ccttatcaaa acggattaat ggaaagtgga gtggtcagag tgctggaagg atgtggaaat    180
ttccaagaga ctcacaaaaa taaccccatc taccaattcc atatagaaaa gactgggccg    240
ttactgattg agctacgagg accaaggcaa tatagccgtt ggatttgagg gtgtaacagt    300
ttctactcta ggagatcctg ggccccatgg ctttctgagg aaatctagtg gtgactatag    360
gtgtgggttt tgctacctgg aattaagaaa atataccttc tgggatcttc aatatcattc    420
ctagtacctt tttgcctaaa caagaaggac cttttttctt ggactttaat agtattatcc    480
ccatcaagat cacacaactt cagtgatgga gaaatctcaa gttactggct tttatactta    540
ccaaacatca gttcttcaaa taaggacgca aatcttcagg acagtaagca gaacaatcag    600
aatggaatta aatctctaaa aaccgtgtta cagtggaatc tggtgcttgt cagggtgttt    660
ggtaagaact gtatatagtc agaattacct aaatcaccta gaggtacctc ggccgcgacc    720
ac                                                                   722
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 129
<211> LENGTH: 290
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  129
tagagcacnt ccatatttta gggctactct aagtaacagn gagacagctg ttttttaacc     60
ctcttctgca agtttgttga cctacatggg ctaatatgga tactaaaaat actacattga    120
tctaagaaga aactagcctt gtggagtata tagatgcttt ncattataca cacaaaaatc    180
cctgagggac attttgaggc atgaatataa aacattttta tttcagtaac ttttccccct    240
gtgtaagtta ctatggttnn gtgggnacaa ctncattcta tanaatatta               290
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 130
<211> LENGTH: 607
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: serine carboxypeptidases
<400> SEQUENCE:  130
ggatcgaccc cggcttccgg cctgttgctg atgctgccgt gcggtacttg tcatggagct     60
ggcactgcgg cgctctcccg tcccgcggtg gttgctgctg ctgccgctgc tgctgggcct    120
gaacgcagga gctgtcattg actggcccac agaggagggc aaggaagtat gggattatgt    180
gacggtccgc aaggatgcct acatgttctg gtggctctat tatgccacca actcctgcaa    240
gaacttctca naactgcccc tggtcatgtg gcttcagggc ggtccaggcg gttctagcac    300
tggatttgga aactttgagg aaattgggcc ccttgacagt gatctcaaac cacggaaaac    360
cacctggctc caggctgcca gtctcctatt tgtggataat cccgtgggca ctgggttcan    420
ttatgtgaat ggtggcttca ganatgatgg ttctcctgaa gaactcttca ntggcncaaa    480
aaaatccaaa agttccattc tacatttnct caaaatccta tggangaaaa aatggcanct    540
gggcattggt ctnaactttn taagggcatc nancaaagga catcaattgc aacttttgcg    600
ggggttg                                                              607
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 131
<211> LENGTH: 357
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: serine carboxypeptidases
<400> SEQUENCE:  131
ggaaggtgat tgtttcgctg gtcctgttga tgcctggccc ctgtgatggg ctgtttcgct     60
ccctatacag aagtgtttcc atgccaccta agggagactc aggacagcca ttatttctca    120
ccccttacat tgaagctggg aagatccaaa aaggaagaga attgagtttg gtcggccctt    180
tcccaggact gaacatgaag agttatgccg gcttcctcac cgtgaataag acttacaaca    240
gcaacctctt cttctggttc ttcccagctc agatacagcc agaagatgcc ccagtagttc    300
tctggctaca gggtgggccg ggaggttcat ccatgtttgg actctttgtg gaacatg       357
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 132
<211> LENGTH: 674
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: serine carboxypeptidases
<400> SEQUENCE:  132
ggctccaacg tctttgtgaa catggaggag gacttcatga agccagtcat tagcattgtg     60
gacgatgttg ctggaggcag ggatcaacgt gacggtgtat aatggacacg ctggatctca    120
tcgtagatac catgggtcag gaggcctggg tgcggaaact gaagtggcca gaactgccta    180
aattcagtca gctgaagtgg aaggccctgt acagtgaccc taaatctctg gaaacatctg    240
cttttgtcaa gtcctacaag aaccttgctt tctactggat tctgaaagct ggtcatatgg    300
ttccttctga ccaaggggac atggctctga agatgatgag actggtgact cagcaagaat    360
aggatggatg gggctggaga tgagctggtt tggccttggg gcacagagct gagctgaggc    420
cgctgaagct gtaggaagcg ccattcttcc ctgtatctaa ctggggctgt gatcaagaag    480
gttctgacca gcttctgcag aggataaaat cattgtctct ggaggcaatt tggaaattat    540
ttctgcttct taaaaaaaac ctaagatttt ttaaaaaaat tgatttgttt tgatccaaaa    600
taaaggatga taatagatat tattttttct tatgacagaa gcaaatgatg tgatttatag    660
aaaaactggg aaat                                                      674
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 133
<211> LENGTH: 1960
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: serine carboxypeptidases
<400> SEQUENCE:  133
cacgcgtccg gccgtgcggt acttgtcatg gagctggcac tgcggcgctc tcccgtcccg     60
cggaaggatg ctgctgctgc cgctgctgct gggcctgaac gcaggagctg tcattgactg    120
gcccacagag gagggcaagg gaacttatgg ggattatgtg acggtccgca aggatgccta    180
catgttctgg tggctctatt atgccaccaa ctcctgcaag aacttctcag aactgcccct    240
ggtcatgtgg cttcagggcg gtccaggcgg ttctagcact ggatttggaa actttgagga    300
aattgggccc cttgacagtg atctcaaacc acgggaaaac cacctggctc caggctgcca    360
gtctcctatt tgtggataat cccgtagggc actgggttca gttatgtgaa tggtaagtgg    420
tgcctatgcc aaggacctgg cttatggtgg cttcagacat ggatggttct cctgaagacc    480
ttcttcagtt gccacaaaga attccagaca gttccattct acattttttc agagtcctat    540
ggaggaaaaa tggcagctgg cattggtcta gagctttata aggccattca gcgagggacc    600
atcaagtgca actttgcggg ggttgccttg ggtgaatcct ggatctcccc tgttgattcg    660
gtgctctcct ggggaccatt acctgtacag catgtctctt ctcgaagaca aaggtctggc    720
agaggtgtct aaggttgcag agcaagtctg aatgccgtaa ataaggggct ctacagagag    780
gccacagagc tgtgggggaa agcagaaatg atcattgaac agaacacaga tggggtgaac    840
ttctattaac atcttaacta aaagcactcc cacgtctaca atggagtcga gtcttagaat    900
tcacacagag ccacctagtt tgtctttgtc agcgccacgt gaagacacct tacacgagat    960
gccttaagcc agctcatgaa tggccccatc agaaagaagc tcaaaattat tcctgaggat   1020
caatcctggg gaggccaggc taccaacgtc tttgtgaaca tggaggagga cttcatgaag   1080
ccagtcatta gcattgtgga ccaagttgct ggaggcaggg atcaaccgtg accggtgtat   1140
taatggacaa gcttggatct catcgtagat accatgggtc aggaggcctg ggtgcggaaa   1200
ctgaagtggc cagaactgcc taaattcagt cagctgaagt gggaaggccc tgtacagtga   1260
ccctaaatct ttggaaacat ctgcttttgt caagtcctac aagaaccttg ctttctactg   1320
gattctgaaa gctggtcata tggttccttc tgaccaaggg ggacatggct ctgaagatga   1380
tgagactggt gactcagcaa gaataggatg gatggggctg gagatgagct ggttatggcc   1440
ttggggcaca gagctgagct gaggccgctg aagctgtagg aagcgccatt cttccctgta   1500
tctaacttgg ggctgtgatc aagaaggttc tgaccagctt ctgcagagga taaaatcatt   1560
tgtctctgga ggcaatttgg aaattatttc tgcttcttaa aaaaacctaa gattttttaa   1620
aaaatttgat tcgtttcgat caaaataaag gatgataata gatattattt tttcttatga   1680
cagaagcaaa tgatgtgatt tatagaaaaa ctgggaaata caggtaccca aagagtaaat   1740
caacatctgt ataccccctt cccaggggta agcactgtta ccaatttagc atatgtcctt   1800
gcagaatttt tttttctata tatacatata tattttttac caaaatgaat cattactcta   1860
tgttgtttta ctatttggtt ggcatatcaa gtatatctga aacacctttt catgtcaata   1920
aatgttcttc tctaacattt ttaaaaaaaa aaaaaaaagg                         1960
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 134
<211> LENGTH: 1000
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  134
cgcggacgcg tgggtgcgtc agaaggttct aacttttgtc atcactatta ccagcattgt     60
catcgttatc gttatcttcg tcatcatcat taccaccgtt atacctgata ctgccataac    120
aatcagaaca ttatgtacag gcacggcata tcttcccaaa gatcttggcc actatggact    180
acgatcttta tttttcttgg agtggcggca atcttgggag taaccattgg tcttcttgtt    240
cattttctgg cagttgagaa gacttactat tatcaaggtg attttcatat ttctggagtc    300
acatacaatg ataattgtga aaacgcagct tcacaagcca gcacaaatct aagcaaagat    360
attgagacta agatgttaaa tgcatttcaa aattccagta tatataagga atatgtcaaa    420
tctgaggtca tcaaacttct gcctaatgcc aatggttcaa atgtgcagtt acagctgaaa    480
ttcaagtttc ctccagcaga aggagttagc atgaggacta aaatcaaggc taaattacat    540
cagatgttga aaaacaacat ggcatcctgg aatgcagttc ctgcttccat taaactcatg    600
gaaatcagca aggctgcttc tgaaatgctt accaacaact gttgtgggag acaagtagcc    660
aacagtatca taactggcaa caaaattgtg aatggaaaaa gctccctgga gggggcatgg    720
ccatggcagg ccagcatgca atggaaaggc cgtcactact gtggagcctc tctgatcagc    780
agcaggtggc tattatctgc agctcactgc tttgctaaga aaaataattc aaaagattgg    840
actgtcaact ttggagttgt agtaaataaa ccatatatga cacggaaagt ccaaaacatt    900
atttttcatg aaaattatag cagtcctggg cttcgatgat ttgccttgtc agcttgttag    960
aagtttcttt tcagagtact tcgtaagatt gcttctgaan                         1000
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 135
<211> LENGTH: 69
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  135
aaagaaaaga atggtggaag ccttttgtga gaacaagccc catttgcagc catggtcacg     60
actcatttc                                                             69
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 136
<211> LENGTH: 472
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  136
ccgcaaacaa gctgggagaa gcacggaatc tgcgctcggg ttccgcagat gcacgaggtt     60
gaggtggctg cgggactgga agtcatcggg cagaggtctc acagcagcca aggaacctgg    120
ggcccgctcc tcccccctcc aggccatgag gattctgcag ttaatcctgc ttgctctggc    180
aacagggctt gtagagggag agaccaggat catcaagggg ttcgagtgca agcctcactc    240
ccagccctgg caggcagccc tgttcgagaa gacgcggcta ctctgtgggg cgacgctcat    300
cgcccccaga tggctcctga cagcagccca ctgcctcaag ccccgctaca tagttcacct    360
ggggcagcac aacctccaga aggaggaggg ctgtgagcag acccggacag ccactgagtc    420
cttcccccac cccggcttca acaacagcct tcccaacaaa gaccaccgca at            472
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 137
<211> LENGTH: 532
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  137
tgtccacccc cgcgtccgat aagccttaat ttctaagata atttaacttt tgttatggga     60
cgggaggtaa gagtgtaaat tttatataca tgaaggtaag atctgagtgt aaactttaca    120
tacatgaagt atgaatggaa ggtagaaaaa aagtcccttt tcgcatgtaa tctctttatc    180
aaagaatttt cttttgacac tttaccactg aagtattttt gtaagtccta aattcgcagc    240
atattgtttc atatttatat gccatcttgc aaatagttct tgctatttta ttcactgctg    300
ttacacttta naaaaattcc agcttgttta cttgcattta tcagtgatgc caaccaagct    360
ttgactgtta acttgaaagc ttgcttctga aatgtnggtg cattttcagg tgacctctta    420
tctctctgaa agttcatacc tattagcagg ctctgtanat attgacatac ttagctttta    480
atacattcta tangtaaatt tatagatttc agaataactt aaaaaattaa tg            532
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 138
<211> LENGTH: 591
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  138
gcttggtgtt cagagtatgt taaagagaaa gggaggtctg gaaggctccc aataaaagac     60
actgagacac agaacattag ctggacatgc agacccagag acccgggacc cagagactcg    120
gagacccgag acctggacac ccagtgggag aagggctggg ctggttcgcc tcccctcccc    180
gtcctcctcc ccactcttcc ccttcctctg cttcctcatc ttcttcctct gtgaaatgcc    240
cctaacccct acaaatagga tttcaggatt tcaaccagtg ttcccaacaa attccatcag    300
ctttagtggt ttctgaaaag cagacagtga cggtgccccc caccacggcc ctgggggctg    360
ttggtcactt acctaccctc accttgaatc tcttggcttg gtagagaaca gtgggctgcc    420
gtagggatgt agaactcgct cagaatagtt ccaccacaga aacccttcgt tttcctcatt    480
gatgagcagg gcctgtgacc aggacgtgac aggcttcant gtggctggcc aggtgacaag    540
gtgttgcctg acttgagaag ccagctcttt caggtggcac tgnccgggcc t             591
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 139
<211> LENGTH: 619
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  139
gatatgcaag cgacgcggac aggccaaaca gtgacagcca cgtagaggat ctggcagaca     60
aagagacaag actttggaag tgacccacca tggggctcag catctttttg ctcctgtgtg    120
ttcttgggct cagccaggca gccacaccga agattttcaa tggcactgag tgtgggcgta    180
actcacagcc gtggcaggtg gggctgtttg agggcaccag cctgcgctgc gggggtgtcc    240
ttattgacca caggtgggtc ctcacagcgg ctcactgcag cggcagcagg tactgggtgc    300
gcctggggga acacagcctc agccagctcg actggaccga gcagatccgg cacagcggct    360
tctctgtgac ccatcccggc tacctgggag cctcgacgag ccacgagcac gacctccggc    420
tgctgcggct gcgcctgccc gtccgcgtaa ccagcagcgt tcaacccctg cccctgccca    480
atgactgtgc aaccgctggc accgagtgcc acgtctcagg ctggggcatc accaaccacc    540
cacggaaccc attccggatc tgtccagtgc ctcaacctct catcgtctcc atgccacctg    600
catggtgtgt atccgggag                                                 619
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 140
<211> LENGTH: 460
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  140
cgcgtccggt gaacttctgt catctccttc tggcttggtt gcctctgaaa ggagggaaag     60
tctcttggta aattatctct tttgtgctgt ttgctgtttc tctgctgccg tctttgcagt    120
tctcctctca ctggttgcag gctttcatag taaggtttgg cgagaaatgt tccaaacatc    180
acattttgga ttctaggctg tcacccctca ttctgtgaaa cgtattagca tgtgttcgcc    240
caagatgact attccttgtg agccagttaa tgatgatatt ctacgccctt cccttctaag    300
ctgtagttca ggaatccagc ccacatagac agactcttgc tttccatggt gtagtcaatg    360
ccaagtgatg catctaggca ggaaaatcta ctctttgctt ttttgggggc aattagtaca    420
tttgtgaagt gcagcatcca agaaacagcc tgttttttca                          460
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 141
<211> LENGTH: 372
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  141
ccgccactgt ggatgaagca gagaaagcaa ttgagctgcg tctggcaaaa attgaccata     60
ctgcaattca cccatttact tgacatgaag attggacaag ggaaatatga gccgggcttc    120
ttccctaagc tgcagtctga tgtactttcc actgggccag ccagcaacaa gtggacgaaa    180
aggaatgccc ctgcccagtg gaggcggaaa gatcggcaga agcagcacac agaacacctg    240
cgtttagata atgaccagag ggagaagtac atccaggaag ccaggactat gggcagcact    300
atccgccagc ccaaactgtc caacctctct ccatcagtga ttgcccagac caattggaag    360
tttgtagagg gc                                                        372
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 142
<211> LENGTH: 313
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  142
cgggggcctg tgctgtgcct cgagcctgac ggacactggg ttcaggctgg catcatcagc     60
tttgcatcaa gctgtgccca ggaggacgct cctgtgctgc tgaccaacac agctgctcac    120
agttcctggc tgcaggctcg agttcagggg gcagctttcc tggcccagag cccagagacc    180
ccggagatga gtgatgagga cagctgtgta gcctgtggat ccttgaggac agcaggtccc    240
caggcaggag caccctcccc atggccctgg gaggcagggc ttgatgcacc aggggacagc    300
tggcctgtgg cgg                                                       313
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 143
<211> LENGTH: 558
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  143
gcccagtgtt tcttttcctt gtcccttccc tcaccaacct ggagttattt tggttgacta     60
tgtcctggct ttggcttctc ctggcaggaa gtcatcaggc atcctctcca ggtgagccga    120
aattccaccc tcccaggttg gacatcatct tttaaaccca atggtctact cccctccttc    180
tttatgaaac agtgatttcc cgtgcagtaa ctctggttct gattttttgt accggcgctt    240
aaattctttc tgtagacatt ggaaagccac aaagaacgtg actgcagtga gcctcccact    300
ggagcagcct taaccaacac tttggccaaa gcccccccac ctcccctgtg tactgtgtgt    360
gtgtttggtg gatacagtat tccttttcag tgtccctaaa gctgtgatgg ggagtcccca    420
cttacctaga aagcattacc agtcacctac tctgcattct ccagatgtta aaccttgttg    480
ttattgttct tttttgcaat gacctattta tttaacctat ttaatattta tttaattttt    540
tactcctgaa atgtttcc                                                  558
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 144
<211> LENGTH: 246
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  144
accgcaacac ccgaggattg aacttccttt gaacagtcca atgcagagca cagggtctcc     60
ccaatgaccc aggaatgatt gcatgtctcc ctcaaggctg cctccacagt tcattttgct    120
gttaatctct actgggtagg aggcctgaca ctggatccgg gttcgcatca tgagcatgca    180
cgcactccag gtcctcgggg tcagtagttc ccaaaagtgc actgttgacc agcgagacat    240
gacgca                                                               246
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 145
<211> LENGTH: 154
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  145
tagcaaaggc ccccccaaac caaccgaaaa aggcggaaac ccgaggaaac cccgggggcc     60
cccaaaaaaa gttgccccca aacccaaaaa aaaagcgggc caccccgggg accggccacc    120
caccaccccc gggggggcaa taggggggcc cccc                                154
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 146
<211> LENGTH: 41
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  146
gttnaaaaaa aaaaanantt tttgggggcc cccccctttt t                         41
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 147
<211> LENGTH: 462
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  147
cccccacatt ccgcccacgc gtccgggtaa aaatgctgaa atgtctgtaa cccagtaata     60
gagcaaacat tatttttacc aacccaaact ctgctggtcc taacatagta atgctatctc    120
acagataatc taatgatatt ctattactgg gttacagaca tttcagcatt tttaggttgg    180
ttttaaatca ctaaaaatat ttattcggat ttgaaggatt taagtgctaa aaatcaatcc    240
atttcttgcc cttcaataat tgtccatgcc tgccttttgt tgtttacatg ctcttctgcc    300
cagactgtta gtaatctagg gacccccttt ggagctgata agtacagttc aaccttttct    360
cctcaaatat ataatgactt taacattcct aagaatatag gtatttctga atgatttaaa    420
tttgaagaat tttaatacat aaaatacaat gtacaaactt tc                       462
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 148
<211> LENGTH: 512
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  148
nttccccttg ccctctacca cgcgtccgcg ccacgcgtgg gttttttttt tgcctcatca     60
aaatttatta agttgtacat atacagtata ttatcagaac aacaccaaag tggctacact    120
tgacagattc tcctaaagtg gacataattt tcctagagat tattattccc cttgataaaa    180
gttgtaatga ttgtgaaagc tttgaaagac aagcttgaag ggccacagca ttgactatca    240
gggcaaggag ctatanatgc catgcacgca gggcccagaa ggcagcagag ccgcaggagg    300
ctgtggcagc cccgtttctg ctgtgagcaa acagtgctat gangagacca acncaaagaa    360
gaaggtgctc ctctccangg gtagggtctt tgggttcacn tccaaaacnc aaaacccccc    420
cccngaaaaa aaaaggaaac aaacccccta cagggtctng gcccccnccc aaaaaanggg    480
ccnntnttgg ccnaaaaagg cccaattnaa at                                  512
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 149
<211> LENGTH: 397
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  149
cgggactcct gcccacttgg gggaaacctt atacccagag gaaaatacac acctggggag     60
tacatttgac aaatttccct taggatttcg ttatctcacc ttgaccctca gccaagattg    120
gtaaagctgc gtcctggcga ttccaggaga cccagctgga aacctggctt ctccatgtga    180
ggggatggga aaggaaagaa gagaatgaag actacttagt aattcccatc aggaaatgct    240
gaccttttac ataaaatcaa ggagactgct gaaaatctct aagggacagg attttccaga    300
tcctaattgg aaatttagca ataaggagag gagtccaagg ggacaaataa aggcagagag    360
aagagacaga ctaaaaatac gaggaaagga gagtggg                             397
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 150
<211> LENGTH: 169
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  150
ttggtgtgga aaccagggtt tcctctctgg gcacaccata acccccggaa aaaacacccc     60
ggggttgtcc attggagact aaggggccac caaagtcacc cggggaggag tcctttccgc    120
cctccaggaa gcccagacag aacatgtttt tagtgatctt gcctgggta                169
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 151
<211> LENGTH: 726
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  151
cccnttttta aaacctgctt cncctttnta atntgtaaag gggnncctct ntcgaaagnn     60
gcacgacntt tgatgagtna acatgtnccg cacaanctgc tgncncnccn gctancnnaa    120
aagantgaag acaaancatc tgaggacana ganaaaactt gangantatn aangaaagaa    180
aggaaatatc tggttctttg atgactttgt tcttgattgt aactcacctg aanccacccc    240
anctatanac atntgttgtg accnacaatc atttccttat ttttanancc agtttganat    300
ggccanaggc atatataaat ncaaatgtca ttataatnaa ttataatnat atntgaaatg    360
caatgtntac tgttatattt ataatgctat gattanatag canaatttta gggtttgtta    420
ttaactcccg attctccnca ganaccnact cnttggncac cacngggaga aatcncatnt    480
attagnaaga nttggctcat atgattatna aagcttgana aatcccatgg tctgccatct    540
gccacctgga aacccccgga aaaaacactt tccttaaatc catcnnaatc caantggcct    600
gcaaaacccc ttccancttc nnttgtctta attantantt gaacnaggac ctccnnngta    660
tccnaagaaa attttcttan cttccgggcc gnngcgaccc acaaanccaa nnggngggaa    720
tttctt                                                               726
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 152
<211> LENGTH: 246
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  152
agggtggagg gggtcagggt gcgttttcgg gcaacagttc ggttccgggt gagctacaga     60
gacatgtagg ggcatttgga gcgtttggaa ctcacacgtc gaagcagtgc gccgccgaca    120
gcagccacct ctctgccacc agcacggccc cgcaacggtg ttcccggcgc cgcagccaca    180
ggtctacctg ccacggccac tccccacggc ccgctgcgct gccgcccaca atcctggtga    240
gcgcgg                                                               246
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 153
<211> LENGTH: 495
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  153
cgcgtccggt cccgcacagt ggtcatggga cgtgcggctg atcatgcgcc aagaccggct     60
atggagtgga agagttgatc tctgcccttc agcgctcctg gcgctaccgt ggggacgtct    120
acttagtggg cgccaccaac gccggcaaat ccactctctt taacacgctc ctggagtccg    180
attactgcac tgccaagggc tccgaggcca tcgacagagc caccatctcc ccttggccag    240
gtactacatt aaaccttctg aagtttccta tttgcaaccc aactccttac agaatgttta    300
aaaggcatca aagacttaaa aaagattcaa ctcaagctga agaagatctt agtgagcaag    360
aacaaaatca gcttaatgtc ctcaaaaagc atggttattg tcgtaggaag agttggaagg    420
acattcttgt attcagaaga acagaaggat aacattccct ttgagtttga tgctgattca    480
cttgcctttg acatg                                                     495
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 154
<211> LENGTH: 525
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  154
gtccggtttt acgtctccat ggtaactgtg ccctgcaccc ctcggtagcc gccctgttag     60
ttttcagtct ccttttcttt ctcaccattt atcacttccc tcactgccct acccaggctt    120
tctctcccac ttccctgact ctgggaataa ctaatattta agcaaggtaa gatgagaagc    180
aaggggtctc agttctagga atacagtgct agttgattgt caggtatgtt gtaaatagac    240
cctctttggc catacactcc atgcctagat gcctcggaga gcatcattct ctgcctaggc    300
aaggccctgc atcccttgcc tcaggccggg ctgagtgtga ctgcagctcc tgaggatggg    360
cctgccctgt ctggggtatg ccgtgatccc tagatacatg ttcccacaag aggtgcctgc    420
tccgtcttcg ctcaccagac actcaggcag gctggcttag tctttgtgcg tggcgatttt    480
gtgctctggg ccctttctct ttttccagcc agtttccatt cactt                    525
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 155
<211> LENGTH: 481
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  155
ccgggacagc tgtgtagcct gtggatcctt gaggacagca nggtccccag gcanggagca     60
ccctccccat ggccctggga ggccaggctg atgcaccagg gacagctggc ctgtggcgga    120
gccctggtgt cagaggaggc ggtgctaact gctgcccact gcttcattgg gtgagtcttg    180
gatccctctc tgctgtgccc cctgccctgc cggcagccct gtcacctggt gccggtccac    240
actgcctctg cacaggcgcc aggccccaga ggaatggagc gtagggctgg ggaccagacc    300
ggaggagtgg ggcctgaagc agctcatcct gcatggagcc tacacccacc ctgagggggg    360
ctacgacatg gccctcctgc tgctggccca gcctgtgaca ctgggagcca gcctgcggcc    420
cctctgcctg ccctatcctg accaccacct gcctgatggg gagcgtggct gggttcttgg    480
g                                                                    481
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 156
<211> LENGTH: 268
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  156
ccacgcgtcc gccatgaaaa tgcctccaaa ctgagatgct ttcagctgag aacagatttg     60
actcacagac attaccaaag aggagcttgt gaatccagga aaagctccag ggggctagct    120
gatctgagca gagagctttc agtgacccat tttcctgtct agactctgcc ttaagctagt    180
ggcaactgct ggggccccag gtacttggga catggaaact cgttggatgg ctgggcagat    240
gtnancctgt ccatgcngtc ngccgacc                                       268
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 157
<211> LENGTH: 519
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  157
cccgttntct acccgtctct tcatctgtcc attcacacat ccttccacac accaacactt     60
cgacctttac tacaggacag gcattctgtt aggtactagg gctccattag tgcagataca    120
gtttctgctt tcagtgggcc cacagctgga tggggcaggc aggggtgaaa tcaacacttc    180
taccttccca tcccccatac ttaggaccag gaataagaaa ggagagctgt ccacactggc    240
tctctggggc ttagcactgg gccacgcttc ctgagagtta ggaccatgct gacactcacc    300
tctctctctc tttctatctc acccatctct gttggcagag tgtggagcga ggcccctggc    360
ttcccggata gttggtgggc agtctgtggc tcctgggcgc tggccgtggc aggccagcgt    420
ggccctgggc ttccggcaca cgtgtggggg ctctgtgcta gcgccacgct gggtggtgac    480
tgctgcacat tgtatgcaca gggcagagag tgtaatccc                           519
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 158
<211> LENGTH: 26
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  158
agacccggcc accggcctgg ggcgcc                                          26
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 159
<211> LENGTH: 424
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: Lon family of ATP-dependent proteases
<400> SEQUENCE:  159
tttttttttt ttttttttgt cagtttttct tttatttgat caaaatttta aaatatgaat     60
tagttacagg cataaaaata taatatatac ttaaaaccaa ggttttcata gaaagaaggc    120
aaacccgtat ttaaaaataa tattaatttt caaaaattaa ataaaaaata accatataaa    180
ttgttttttc atacttactg gaagaacaag acctctcagt gtaatttctc cagtcatggc    240
tacatctgaa cgtaccagcc gcccactaaa aagtgaggcg agacaggtta ctatggtaac    300
tccagcagat ggtccatctt ttgtgacagc tccagctggg aagtgcagat ggatgtctgt    360
gttgtcaaga agatcaaaac ttccaaagct ttaaaaagga aaaagggact ttaatgtaga    420
aaaa                                                                 424
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 160
<211> LENGTH: 958
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: Lon family of ATP-dependent proteases
<400> SEQUENCE:  160
gcaatcctat gctttgttgg ccctcctgga gttggtaaaa caagtgtggg aagatcagtg     60
gccaagactc taggtcgaga gttccacagg attgcacttg gaggagtatg tgatcagtct    120
gacattcgag gacacaggcg cacctatgtt gggcagcatg cctgggtcgc atcatcaacg    180
gcttgaagac tgtgggagtg aacaacccag tgttcctatt agatgaaggt tgacaaactg    240
ggaaaaagtc tacagggtga tccagcagca gctctgcttt gaaggtgttg gatcctgaac    300
aaaaccataa cttcacagat cattatctaa atgtggcctt tgacctttct caagttcttt    360
ttatagctac tgccaacacc acttgctacc attccagctg ccttgttgga cagaatggga    420
gatcattcag gttccaggtt atacacagga ggagaagata gagattgccc ataggcactt    480
gatccccaag cagctggaac aacatgggct gactccacag cagattcaga taccccaggt    540
caccactctt gacatcatca ccaggtatac cagagaggca ggggttcgtt ctctggatag    600
aaaacttggg gccatttgcc gagctgtggc cgtgaaggtg gcagaaggac agcataagga    660
agccaagttg gaccgttctg atgtgactga gagagaaggt tgcagagaac acatcttaga    720
agatgaaaaa cctgaatcta tcagtgacac tactgacttg gctctaccac ctgaaatgcc    780
gattttgatt gatttccatg ctctgaaaga catccttggg cccccgatgt atgaatggag    840
gtatctcagc gtttgagtca gccaggagta gcaataggtt tggcttggac tcccttaggt    900
ggagaaatca ttttcgtgga ggcgagtcga ttggatggcg aggccaatta actctgac      958
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 161
<211> LENGTH: 1402
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: Lon family of ATP-dependent proteases
<400> SEQUENCE:  161
ttttttcgat ttttatcagt ttactaaatc aacatcctta aattcctata ctaaacatta     60
gccactactt gaggttaatt actgttgtga ttatgtttat aaaacaggga catcttgcat    120
acccctaatg gtgtgaataa aatcaaactg tgtcagaccc tttggagcac ttcaatactt    180
aaaaattctt aaaaaattga gatttggacc tacagtttgc tatttaacag accaggtctg    240
gtcttgacag taaagccacc atccaaaagc tgcattaaga acctcaatcc aggcagcttg    300
ctgtgacaaa acttaaatcc tgtcgtacgt tgcctgggat tccctcaagg tctttttcat    360
ttctccgagg aataatgact tggcttcagt cccgctctgt gtgccgccag cactttgtct    420
ttaattccac ccactggaag aacaaagccc tctcagcgta atttccccag tcaatggcta    480
catcttgagc gcaacaagcc gcccactgaa aagtgaggcg agacaagtta ctatggtaac    540
accagcagat gggtccatct tttgtgacag gctccagctg ggaagtgcaa gatggatgtc    600
tgtgttgtca agaagatcaa aacttccaaa agctttaaaa aggaaaaagg gacttttaat    660
gtagaaaaat taaacctgtt ttctttttct cctaaaaaaa aagtcacaac caaaaatgaa    720
tgttttgggt aaatgaattc ttcaaaatat tggtggacag tacaatttgg gtgagggtgt    780
ggaagaacag ttccattcta ctctaagtcg tattaaaaca aaataaacct tttgaattag    840
tttctagttc aggcactagt caaatagtcc tgaaatggga actaggattt ccacaggggt    900
tcaaaacggt gtgtactttg ctagatgtgt aactggcagt ctcgagctca tgccagtctc    960
cgccatggaa ggtaccgcct ccctgggtca aggcctgcct tggccggttg caaggctccc   1020
taccattggt cagctgggta cttctttgcg ttgctgcgga gcccagctga atagcgaggt   1080
gggcggactc cttcatcacg tccccgagct ggccggtcag agttaactgg ccctcgccat   1140
ccattcgact cgcctccacg aacatgattt ctccacctaa gggagtccaa gccaaaccta   1200
ttgctactcc tggctgactc aaacgctgag ataccttgaa agaagaagaa tgatcagagt   1260
tgggttggca aatgctaaag gtgactgata ccacacaatc ctgcaagagt cggctgactc   1320
cacagaagac ttcagccact tacctcaaag tccttgttac ctaacatgat tctgcgtcac   1380
attcagcact tactctctgg ct                                            1402
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 162
<211> LENGTH: 536
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  162
ccggtttttc taaatagacc cttatgggag tttgaaaata aatactcaca tatttcacta     60
cttaaattat tcccaagatt tgaatttatt ttaaaatttt aatagccacc aagaatgtgg    120
acatatgaaa attcaagaac ctaaaaaata ccagttttga atgagttttt gtggttttgg    180
tttttttttt aattattaca aatctatgtg taaaatctag atatttgaag tttgagatct    240
gatgagaatg gttgttataa actttatttt aaaaccaaat ttaggtgttc ttacatattt    300
aaatactgga aagtcattat aatagttttg gttctttgaa ttggtagaca attagtagag    360
tataattggt taggaggcag ggcttattaa gtggttatta accgctgaca tcagacaaac    420
ccaaatctgt agaattctaa ccttctaaca cctgtgacag tattaccctc ttcttggatt    480
atagatttag aactgattta ctcaattgca ctcttaacta atggtaaaag cttact        536
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 163
<211> LENGTH: 908
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  163
tccgatagta caataaatat ttgtgttaat gagaactaat attctgacta attatctaaa     60
gtgtttcact agtacaccag gaaactacag attgagatta gggggtggga ggaaagaaac    120
ctgggctaga gattaaaaca ttcctaaatt tagcanaatt tcagaaatga tttttgcaga    180
ttcattagaa aagaaaaatt gtcatttaat cttaagtttt ggatgtagct cacatgtcac    240
caccaccaga tagtgttaca gcatgtatcc atcatgttgc attgacacat caaacttgtg    300
tgtgtttgtt ttgattgcca aaagggctta atatcagttg tacaatcttt ctgaacttta    360
tagttcctgg ctccaggaaa gatggccttt gctattgaag ccaacttctt ccccatgctg    420
tttatcttta ccagaactta agagatcttt gtttcctatt agcaggtttt ccattgataa    480
ggaaaaagaa caagtagtgt gttgtcttta ttcttgatac aacaccacct ccggtgcttt    540
gcaacctgga accaaaacca taccatgaga gagaggggga aaaaaatcta tgcacttaac    600
ctacaaaatc tctggtgatg acagttgtat tgttgctatt acatggcata acggtctatt    660
atgtggtagg aaaatatagc ctgctaaatc ctacttaagt tgatccactt taaactgagt    720
aactgtataa aacatctatt gaaaattctt ttccttttga cttagattct gccttacatc    780
aatttttgca tttttggtaa aaaaaaaacc ctactacgtt tgactctaac ctgatacttg    840
ctctctaatg gctcttaata tatcctttga aatcngctat ttccatttta tcagactttt    900
accanaan                                                             908
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 164
<211> LENGTH: 442
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  164
acatttaggg actctgctgt cctttattgg tgttgttaat gctcagtaat atgaaggaag     60
cagaagcata gaccagaggg gaaaataaga aaatagatag attatgttaa cacggtgaag    120
agacaaagat tccactgtca ccaagaatgt catattgcta aacttcaatt tagggggtta    180
cttaaaggca tgaccttatg gaaatttaat gatatgttat ggttcatcag aactcgtcag    240
ttggccccaa gctgcgataa tcaacttttc aatgtcggac tcatttactc ctcgaagaat    300
cctgaaatag ccattctctc cccatgactt tccccaggaa ttggcagcaa tccaaaattt    360
ttctttctgc ccttgtgctc ctctcagtgt gccccatcca gtgagtttga ctgcatgtgt    420
ctgaagcttt cgatattttt cn                                             442
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 165
<211> LENGTH: 492
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  165
cccgggacaa caaaatgatg gtttctatct gtgaacagaa gctgcagcac ttcagtattg     60
gacaacaact tgtctatgtt ttgggaaccc aaatagtgct gtcttcctgc tcatcctctg    120
cttgggaatg atgtcagctg ctccaccccc tgatccaagt ttggataatg agtggaaaga    180
atggaagacg aaatttgcaa aagcctacaa tctgaatgaa gaaagacaca gaagactcgt    240
gtgggaggag aataagaaga aaattgaggc acacaatgca gactatgagc agggcaagac    300
cagcttctac atgggcctga atcaatttta gtgacttgac tccagaagaa ttcaagacaa    360
attgctatgg aaactcactg aatagaggaa gaaatggctc ctgatttgcc tgaatatgaa    420
gatttgggaa agaacagcta tctgacacct ggaagggctc agccagagta acagctgtgg    480
cttgactggt an                                                        492
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 166
<211> LENGTH: 493
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  166
gccccgcgga cgcgtgggcg gacgcgtggg gatgatattg cccttgtgca gcttgctgaa     60
gaagtttctt ttacagagta cattcgtaag atttgtcttc ctgaagccaa aatgaagctc    120
tcagaaaatg acaatgttgt agttacaggt tggggaacac tttatatgaa tggttcattt    180
ccagtgatac ttcaagaagc ctttttgaag attattgaca acaaaatttg caatgcctca    240
tatgcatact ctggctttgt gactgattca atgttatgtg ctggatttat gtcaggagaa    300
gctgatgcat gtcagaatga ttctggtgga ccactagctt accctgattc cagaaatatc    360
tggcatcttg ttggaataag taagctgggg tgatgggatg tggtaaaaaa gaataagcca    420
ggtgtctatc ttcgagtgac ttcttatcgc aattggatta cattcaagac tggactctga    480
aaaaaaaaaa aaa                                                       493
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 167
<211> LENGTH: 56
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: trypsin-like serine proteases
<400> SEQUENCE:  167
cccgcgancg aggacgcgtg ggcggacncg tgggtcgngg gctcagctgg tccggc         56
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 168
<211> LENGTH: 418
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: caspase family of apoptosis regulating
proteases
<400> SEQUENCE:  168
ccgctgggcc ctgggctttg agaccaccgt gagaacggac cctacagccc aggctttcca     60
ggaggagctg gcccagttcc gggagcaact ggacacctgc aggggccctg tgagctgtgc    120
ccttgtggcc ctgatggccc atgggggacc acggggtcag ctgctggggg ctgacgggca    180
agaggtgcag cccgaggcac tcatgcagga gctgagccgc tgccaggtgc tgcagggccg    240
ccccaagatc ttcctgttgc aggcctgccg tgggggaaac agggatgctg gtgtggggcc    300
cacagctctc ccctggtact ggagctggct gcgggcacct ccatctgtcc cctcccatgc    360
agatgtcctg cagatctacg ctgaggccca aggcagctcc tgcaggggca cccctcca      418
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 169
<211> LENGTH: 493
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: caspase family of apoptosis regulating
proteases
<400> SEQUENCE:  169
ccgggctaga ggtgttttgt acaaattata tataagccag cctgatctac caacatgcca     60
cagagaatca caatcaacag tgtggggaaa gtcagggcag tggaagtgga tgcactcttt    120
ttattttgaa ggcttaaacc aaattgtctt ggaattaaag ctgtatttct gcagctttcg    180
gtacagagaa aaagaggaaa gtgaagctgt gtcagtttta acattagcta tatcaacatg    240
tttaagaaag atagatgaag tcatttgcat aaaggtacag cattgaaata ctatgttgtg    300
tttgttttta catttttgca ttaaaaaaaa acatgccgta aaagccaagt taaatttcat    360
attaaagcaa gttctagtgt atgtgttgag ttcctggtaa tcacatactt gttcacatct    420
acaccgtact tcatagtatg atttgtcagg ggagggattg tggggtgaca gttttacatt    480
tactttttct tct                                                       493
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 170
<211> LENGTH: 187
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: caspase family of apoptosis regulating
proteases
<400> SEQUENCE:  170
ttaaaatcca gcccaccgtg ctgcctctcc aagacacgtc acagggaact tgaccacaga     60
acccaaggag atgcttctcc acaggtgctt tgctgacaac atcaccctgc accttctgat    120
atcacagcca agaggacact gtcaaggatg cgtgacagtc tctgaaccac agttacccac    180
ggtgtgc                                                              187
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 171
<211> LENGTH: 823
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: prolyl oligopeptidases
<400> SEQUENCE:  171
gtcaaataga aattgacgat caggtggaag gacatccaat atctagcttc tcgatatgat     60
ttcattgact tagatcgtgt gggcatccac ggctggtcct atggaggata cctctccctg    120
atggcattaa tgcagaggtc agatatcttc agggttgcta ttgctgggtc cccagtcact    180
ctgtggatct tctatgatac aggatacacg gaacgttata tgggtcaccc tgaccagaat    240
gaacagggct attacttagg atctgtggcc atgcaagcag aaaagttccc ctctgaacca    300
aatcgtttac tgctcttaca tggtttcctg gatgagaatg tccattttgc acataccagt    360
atattactga gttttttagt gagggctgga aagcagtatg atttacagta tctttatttt    420
ttgttgttgg taagatctat cctcagggag agacaccggc ataagagttc cctgaatcgg    480
ggagaacatt atgaactgca tcttttggca ctaccttcaa gaaaaacctt ggatcacctt    540
attgctgctc ctaaaattga tataattttg acctgtgtag aactctctgg gtatacactg    600
gctatttaac caaatgagga ggtttaatca acagaaaaca cagaattgat catcacattt    660
tgatacctgc catgtaacat ctactcctga aaataaatgt ggtgccatgc aggggtctac    720
ggtttgtggt agtaatctaa taccttaacc ccacatgctc aaaatcaaat gatacatatt    780
cctgagagac ccagcaatac cataagaatt actaaaaaaa aaa                      823
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 172
<211> LENGTH: 502
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: prolyl oligopeptidases
<400> SEQUENCE:  172
ggtggctata ttgcatcaat gatcttaaaa tcagatgaaa agctttttaa ttgtggatcc     60
gtggttgcac ctatcacaga cttgaaattg tatgcctcag ctttctctga aagatacctt    120
gggatgccat ctaaggaaga aagcacttac caggcagcca gtgtgctaca taatgttcat    180
ggcttgaaag aagaaaatat attaataatt catggaactg ctgacacaaa agttcatttc    240
caacactcag cagaattaat caagcaccta ataaaagctg gagtgaatta tactatgcag    300
gtctacccag atgaaggtca taaccgtatc tgagaagagc aagtatcatc tctacagcac    360
aatcctcaaa ttcttcaagt gattgtttga agggaggaat atctgtggct accacaggaa    420
ccagaaggaa gatggaataa tgggaccgta tttattacag aactggaagg gaatattgga    480
ggcttcatgg aaacctgaca ag                                             502
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 173
<211> LENGTH: 706
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: lysosomal Pro-X carboxypeptidase
<400> SEQUENCE:  173
ctgctgctgg cgctcgggct gcgcggcctc caggcggggg cccgcacggc ccccggggct     60
ccgctccctg ggccccggtc ctgctgctgg cgctcgggct gcgcggcctc caggcggggg    120
cccgcagggc cccggacccc ggcttccagg agcgcttctt ccagcagcgt ctggaccact    180
tcaacttcga gcgcttcggc aacaagacct tccctcagcg cttcctggtg tcggacaggt    240
tctgggtccg gggcgagggg cccatcttct tctacactgg gaacgagggc gacgtgtggg    300
ccttcgccaa caactcgggc ttcgtcgcgg agctggcggc cgagcggggg gctctactgg    360
tcttcgcgga gcaccgctac tacggggaag tcgctgccgt tcggtgcgca gtccacgcag    420
cgcgggcaca cggagctgct gacggtggag caggccctgg ccgacttcgc agagctgctc    480
cgcgcgctac gacgcgacct cggggcccag gatgcccccg ccatcgcctt cggtggaagt    540
tatggggggg atgctcagtg cctacctgag gatgaagtat cccacctggt ggcggggcgc    600
tggcggcaaa cgcgcccgtt ctagctgtgg aaggcttggc gacttcaaca gtctttncng    660
acgtacggcg gactttangg caaatcccaa tgcccccagg gggggn                   706
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 174
<211> LENGTH: 478
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: lysosomal Pro-X carboxypeptidase
<400> SEQUENCE:  174
tttacatggc caggcctcca ggcgtttatt cagccccttc cctctgccgc cagctgcttg     60
agtgaagccc ccactccatg aggagccttg agacccctcc agtcctgtgc tcagaggctg    120
agtctgggcc cccccacgca gagctggctg ctgctcacgc ctggctgcct ttacccactc    180
gccgatgatg gtggcctcca gcttccgcgc ctcaaccacg gaagcaggat cttctgggtg    240
ggaggctctg aggtcgaggt ggtgcgctcc cccctggatg gtgacggcga tgactgaggc    300
actcaggttc ctccgaatcc cgccccctgc ccaggggtcc aggttcccgt tggagaagat    360
gatgttgctg gcggctctaa gatcgctggc ggagctcgtc agtgaagggc aggtcggnga    420
acatatcngt cacatttgtg ctggcgaagg tcanngtgat ctcngtgcan ggcctgta      478
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 175
<211> LENGTH: 703
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: lysosomal Pro-X carboxypeptidase
<400> SEQUENCE:  175
ggtccgctgg gagttcggca cctgccagcc gctgtcagac gagaaggacc tgacccagct     60
cttcatgttc gcccggaatg ccttcaccgt gctggccatg atggactacc cctaccccac    120
tgacttcctg ggtcccctcc ctgccaaccc cgtcaaggtg ggctgtgatc ggctgctgag    180
tgaggcccag aggatcacgg ggctgcgagc actggcaggt gccctttccc ccggccccag    240
atgggcaagt gtggagaccc caggcttggc ttgggtcctg gggccgggtg gggcgaggat    300
ccgcagcccg gccaggggct ttgcctcctg ccccagggct gtggtggggt ggacagcacg    360
accttcccag aaaccctggg ggaggcaggg gccgtccctg gggaccctct cagcactggc    420
tgtagccagg cccagcttgg gtgggtgctg cccaaggggc cccttggggt ccccagcatg    480
gagggcaaca gagggcagca ggccccaccc tgccccgtgg agagccgggg ggccctcaac    540
agtcaggccc ggggctggca gcacagacac cgccgacctc caagcaggta gcctggaggg    600
ccttcctcac tgggacctac agatcccaga gccccagatc ccctgcagga ccattccgag    660
gggggacagg ttggtggccc ggagcccgcg gtgtgtctgt gtg                      703
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 176
<211> LENGTH: 1049
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: lysosomal Pro-X carboxypeptidase
<400> SEQUENCE:  176
tttttttttt tttttttgcc aggcctccag gcgtttattc agccccttcc ctctgccgcc     60
agctgcttga gtgaagcccc cactccatga ggagccttga gacccctcca gtcctgtgct    120
cagaggctga gtctgggccc cccacgcaga gctggctgct gctcacgcct ggctgccttt    180
acccactcgc cgatgatggt ggcctccagc ttccgcgcct caaccacgga agcaggatct    240
tctgggtggg aggctctgag gtcgaggtgg tgcgctcccc cctgggatgg tgacggcgat    300
gactgaggca ctcagggttc ctccgaatcc cgccccctgc cccaggggtt ccagggttcc    360
cgttgggaga agatgatgtt gctgggcggc tctgagatct ggtagtcccc aggccctggc    420
cgttcggggc cggtgccgca gcccagtggg gtcagcacag cttgtggtag agccggtaga    480
tgtcggtagc agtgctcgga agcccgaggc gttgtagacc agccctgcca gtgctcgcag    540
ccccgtgatc ctctgggcct cactcagcag ccgatcacag accaccttga cggggttggc    600
agggagggga cccaggaagt cagtggggta ggggtagtcc atcatggcca gcacggtgaa    660
ggcattccgg gcgaacatga agagctgggt caggtccttc tcgtctgaca gcggctggca    720
ggtgccgaac tcccagcgga ccgtgtcgta ggctccctgt aggaacaagt ccttgatctg    780
tcggaacgct tcccgcacac cctgggtgca tttgggactc tggccctcaa agtccgccgt    840
gacgtcccgg aagaactggt tggagtcgcc gaggcctgcc acagctagaa cgggcgcgct    900
ggccgccagc gcccccgcca ccaggtgggg atacttcatc ctcaggtagg cactgagcat    960
ccccccataa cttccaccga aggcgatggc gggggcatcc tgggccccga ggtcgcgtcg   1020
tagcgcgcgg agcagctctg cgaagtcgg                                     1049
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 177
<211> LENGTH: 279
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc proteases
<400> SEQUENCE:  177
gacctgatgc tatcagaaga ggatccgggg actatgctct ccatataaca nagagattaa     60
tagaatntta tgaagactac tntaaagtgc cctatacctt gccaaaacta gatcttttan    120
ctgtgcctaa gcatncgtat gctgctatgg agaactgggg actaagtntt tttgtggaac    180
aaagaatact gctggatccc agggtnacat ctatntntta ttngctggat gtcaccatgg    240
tcattgttca tgagatatgt caccagaggt ttggtgacc                           279
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 178
<211> LENGTH: 673
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: thimet oligopeptidase
<400> SEQUENCE:  178
cgagcagcaa gtacagaagc agacaaaaga ctttctcgtt ttgatattga gatgagcatg     60
agaggagata tatttgagag aattgttcat ttacaggaaa cctgtgatct ggggaagata    120
aaacctgagg ccagacgata cttggaaaag tcaattaaaa tggggaaaag aaatgggctc    180
catcttcctg aacaagtaca gaatgaaatc aaatcaatga agaaaagaat gagtgagcta    240
tgtattgatt ttaacaaaaa cctcaatgag gatgatacct tccttgtatt ttccaaggct    300
gaacttggtg ctcttcctga tgatttcatt gacagtttag aaaagacaga tgatgacaag    360
tataaaatta ccttaaaata tccacactat ttccctgtca tgaaganatg ttgtttccct    420
gaaaccagaa naaggatgga aatggctttt aataccaggt gcnaagagga aaaccacctn    480
gttttggngc agcttctccc nctgcgaaac canggtgggc aaacttctcc ggttttttcc    540
canattgctg aacttccctn ccctggaaat tgaaacncng gcccaaganc nccaancccg    600
ggtttaccnc ccttcttgaa tnaattttag ccccnaaatt ttaaancccc tngggtttaa    660
nccaaaccaa aaa                                                       673
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 179
<211> LENGTH: 505
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: asticin/m 12a metalloproteases
<400> SEQUENCE:  179
gcttggatga cttctatgtg aaggggttct actgtgcaga gtgccgagca gctggtacgg     60
aggagactgc atgcgatgtg gccaggttct gcgagcccca aagggtcaga ttttgttgga    120
aagctatccc ctaaatgctc actgtgaatg gaccattcat gctaaacctg ggtttgtcat    180
ccaactaaga tttgtcatgt tgagcctgga gtttgactac atgtgccagt atgactatgt    240
tgaggttcgt gatggagaca accgcgatgg ccagatcatc aagcgtgtct gtggcaacga    300
gcggccagct cctatccaga gcataggatc ctcactccac gtcctcttcc actccgatgg    360
ctccaagaat tttgacggtt tccatgccat ttatgaggag atcacagcat gctcctcatc    420
cccttgtttc catgacggca cgtgcgtcct tgacaaggct ggatcttaca aagtgtgcct    480
gcttggcagg ctatactggg cagcg                                          505
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 180
<211> LENGTH: 696
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: astacin/m 12a metalloproteases
<400> SEQUENCE:  180
cgtccgntcc gtctcctcct ctctctctcc atctgctgtg gttatggcct gtcgctggag     60
cacaaaagag tctccgcggt ggaggtctgc gttgctcttg cttttcctcg ctggggtgta    120
cgcttgtgga gagactccag agcaaatacg agcaccaagt ggcataatca caagcccagg    180
ctggccttct gaatatcctg caaaaatcaa ctgtagctgg ttcataaggg caaacccagg    240
cgaaatcatt actataagtt ttcaggattt tgatattcaa ggatccagaa ggtgcaattt    300
ggactggttg acaatagaaa catacaagaa tattgaaagt tacagagctt gtggttccac    360
aattccacct ccgtatatct cttcacaaga ccacatctgg attaggtttc attcggatga    420
caacatctct agaaagggtt tcagactggc atatttttca gggaaatctg aggaaccaaa    480
ttgtgcttgt gatcagtttc gttgtggtaa tggaaagtgt ataccagaag cctggaaatg    540
taataacatg gatgaatgtg gagatagttc cgatgaagag atctgtgcca aagaagcaaa    600
tcctccaact gctgctgctt ttcaaccctg tgcttacaac cagtccagtg tttatcccgt    660
ttaccaaagt tacacttgcc tcccgaatct ttaaan                              696
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 181
<211> LENGTH: 498
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  181
ttatttttgt gtttttgaag atttatttca gagtgagcat cagcgaccta caagaacctg     60
ggacagaagc caatgcctcc cgtttccctg tgatgtgaaa caggaccctg tgcttcctgt    120
ggacttcaag aaatgtggac ttgagctttg ccatcccttc ccctgatcct gtttcataga    180
ttttgctgtt atattctctg tatctttaca gggatcggga ggctgaatta gtgttattca    240
gggttagtaa ctgtcccttc cttaacggtg gtggtcctga tagttcgcac atttttggct    300
gtcccaaaga gcagtgcaat tatgaaggcg taaatacgac caaagaccac tctcagatac    360
atcactgatt gctggctttg tttgacggaa cgtgttcttt ttggaggtgg cccgctgttg    420
acactcccac cagcacctct tcttaggcac agtggaggat cccagcctat atggcaatgg    480
cagttccttc tgttgtgn                                                  498
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 182
<211> LENGTH: 86
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  182
gacgcgtntg gggcnncccc tcncnagaaa annnnnnncc cnnattnttc ccccnncccn     60
gccccctatn tgcngaaagg gggggc                                          86
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 183
<211> LENGTH: 86
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  183
gacgcgtntg gggcnncccc tcncnagaaa annnnnnncc cnnattnttc ccccnncccn     60
gccccctatn tgcngaaagg gggggc                                          86
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 184
<211> LENGTH: 99
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  184
ctgtgctcgc cttcagcgcn ngcccagccc nacgtccgcg ccccggtggt gggcccgacg     60
cccgcattcc gcccgtgtcc atgcgcagaa ctcccgccc                            99
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 185
<211> LENGTH: 558
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  185
gggatcgacc cccgtctgcc cacgcgtccg tctacccccc cccttttttt tctttttttt     60
tttttttttt tttttttttt tttccgggca ccaacgttgg ttttaatggc atcaacaccc    120
agaaggtcac acgtcanttc tggttggcaa cgtctagggg tgaggggctg tggcctccat    180
tcggccccac agcctttgaa aactggctgc ccggtcccac ccgcttcccg ccccgcccca    240
ctgaaaaaac actaaacnat tgcactgaca gacanacccc aaaacgcccg gcctcccaca    300
cacccacggg gctgtcaaan tcaaccaggg ctttggcntc actcggcggt ggcccggggc    360
tgcccccaaa atantgttta tcaaatntga cacaggttca tttacaaact ggggctctgg    420
aaggtctact tctgtggctc taaaaaactt gtctctcatg gcttctctcg gaatnccngg    480
aanttgggcc ctggataacc ctgttgtagg ttggttgggt ttattttntt aaggaaattn    540
ttaaggcatt ttggtaan                                                  558
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 186
<211> LENGTH: 506
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  186
cgaaagccac ccctaggcca attgcctgga tctcctcccc tctcccttct ttaaacgagc     60
ttgcctccct cctgccaagt ttgagggcaa ggctaagaaa tgtcagccac ggaaacaact    120
ctattatctg gtgactttgg gtaatgtgaa tcagtgcctg aggacctttg ctgtgtcctt    180
ggtacagaac catccacttg acctaactac ctcccctggc cgcgctctcg ctcttctctt    240
ctttgttaag ccaacaacta tcaccctctc ctactcttct tctccctgcc ccctggaggg    300
cactgtgttt ggttgtgcaa atgtatttac tatgcgtgtt tccagcagtt ggcattaaag    360
tgcctttttc taataaaatc aagtttatta tgacagtttc ctgatggttg aaagtaagca    420
tcttgataaa gggtcaccat taaaaaaaaa ttttgcataa aggtgctgca tgggttgggg    480
tagccccgcc cccacctgaa aactgn                                         506
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 187
<211> LENGTH: 669
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of matelloprotease
<400> SEQUENCE:  187
tttagtaggg ctttttattg tttttaggcc attgcctgct cagtcccgac agcattcccc     60
cttcttgaaa gtagggcttt ttattgtttt taggccattg cttgctcagt cccgacagca    120
ttcccccttc ttgaaacttc actatagctg ctgacactct tctgaacttt ttctgacttg    180
atactctgaa ttaaaccaag tataagtgtc attttcttct aagagaatat tagtgtcagc    240
atatttttct tcataaatct tgtgtataaa tcctgataac agcctccatc ggttcaattc    300
catatgagat gtttttcagc tgcattgttc ccctgagtcc tgaacatacg ctgagagtca    360
caagagaatt tggaataccc gcaacatatc cattataaat gcaatccatc tgaactagca    420
gaggtttgga atgacggatg tcattttcgt cataagaatt aataacagaa gctgaagata    480
aaattgatag tatgttgagg aggagttttt gcatccgatg atgaaatctt catgtaaata    540
acattatgtt ctggatctgt ttttgcatcc gatgaagaaa tcttctctgg aaatgtggtc    600
cgcaggaaga ttttatgagg attgaggtct gcatgcatcc caccaagtcc agtgagaagc    660
accagaagn                                                            669
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 188
<211> LENGTH: 930
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: thimet oligopeptidase
<400> SEQUENCE:  188
gcctccnaaa tgtggaaact gactttgtag aggtgccatc gcaaatgctt gaaaattggg     60
tgtgggacgt cgattccctc cgaagattgt caaaacatta taaagatgga agccctattg    120
cagacgatct gcttgaaaaa cttgttgctt ctaggctggt caacacaggt cttctgaccc    180
tgcgccagat tgttttgagc aaagttgatc agtctcttca taccaacaca tcgctggatg    240
ctgcaagtga atatgccaaa tactgctcag aaatattagg agttgcagct actccaggca    300
caaatatgcc agctaccttt ggacatttgg cagggggata cgatggccaa tattatggat    360
atctttggag tgaagtattt tccatggata tgttttacag ctgttttaaa aaagaaggga    420
taatgaatcc agaggttgga atgaaataca gaaacctaat cctgaaacct gggggatctc    480
tggacggcat ggacatgctc cacaatttct tgaaacgtga gccaaaccaa aaagcgttcc    540
taatgagtag aggcctgcat gctccgtgaa ctggggatct ttggtagccg tccatgtctg    600
gaggacaagt cgacatcacc atgtgttact ggcctggaaa ctgaagggag ttttgcaagt    660
gaaaatttag atttctattg acatcctttt gttttctaat tttaaaaatt ataaagatgt    720
aaatggaatt ataaatactg tgacctaaga aaagacccac tagaaagtaa ttgtactata    780
aaatttcata aaactggatt tgatttcttt ttatgaaagt ttcatatgaa tgtaacttgg    840
attttttact attataatct aggataatat gatataagga gggcctaaga atttttaaat    900
tggaatccat atatatggta taatttgggn                                     930
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 189
<211> LENGTH: 507
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: asticin/m 12a metalloproteases
<400> SEQUENCE:  189
cggtttgatc acttggaagt tcgagatggg ccatttggtt tctctcctct tatagatcgt     60
tactgtggcg tgaaaagccc tccattaatt agatcaacag ggagattcat gtggattaag    120
tttagttctg atgaagagct tgaaggactg ggatttcgag caaaatattc atttattcca    180
gatccagact ttacttacct aggagattgt cagttcgagc tctcgggagc tgatggaata    240
gtgcgctcta gtcaggtaga acaagaggag aaaacaaaac caggncaagc cgtttgattg    300
catctngacc nttaaagcca ctccaaaagc taagatttat ttnaggttcc nagattatca    360
aatgggagca ctcaaatgaa tgcaagagaa actttcgttg ccagtctatg atgggaagca    420
gtttcttttt naaaacccga agggcccaag tttttncagc actgttggcc cattnatgtt    480
aattgntttt aaaanccggg aatttgn                                        507
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 190
<211> LENGTH: 512
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: astacin/m 12a metalloproteases
<400> SEQUENCE:  190
tcgagcggcc gcccgggcag gtactggtag tggaagggat tgccgtggcc caaaaaaacc     60
caagatggac aaaatattgg aatcaagcat attcctgcaa cccagtgtgg catttgggtt    120
cgaaccagca atggaggtca ttttgcttcg ccaaattatc ctgactcata tccaccaaac    180
aaggagtgta tctacatttt ggaagatcgt tactgtggcg tgaaaagccc tccattaatt    240
agatcaacag ggagattcat gtggattaag tttagttctg atgaagagct tgaaggactg    300
ggatttcgag caaaatattc atttattcca gatccagact ttacttacct aggaggtatt    360
ttaaatccca ttccagattg gtcagttcga gctctcggga gctgatggaa tagtgcgctc    420
tagtcaggta gaacaagagg agaaaacaaa accaggccaa gccgttgatt gcatctggac    480
cattaaagcc acttcaaaag ctaagattta tn                                  512
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 191
<211> LENGTH: 933
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: astacin/m 12a metalloproteases
<400> SEQUENCE:  191
cgtccgaagg gattgccgtg gcccaaaaaa cccaagatgg acaaaatatt ggaatcaagc     60
atattcctgc aacccagtgt ggcatttggg ttcgaaccag caatggaggt cattttgctt    120
cgccaaatta tcctgactca tatccaccaa acaaggagtg tatctacatt ttggaagctg    180
ctccacgtca aagaatagag ttgacctttg atgaacatta ttatatagaa ccatcatttg    240
agtgtcggtt tgatcacttg gaagttcgag atgggccatt tggtttctct cctcttatag    300
atcgttactg tggcgtgaaa agccctccat taattagatc aacagggaga ttcatgtgga    360
ttaagtttag ttctgatgaa gagcttgaag gactgggatt tcgagcaaaa tattcattta    420
ttccagatcc agactttact tacctaggag gtattttaaa tcccattcca gattgtcagt    480
tcgagctctc gggagctgat ggaatagtgc gctctagtca ggtagaacaa gaggagaaaa    540
caaaaccagg ccaagccttt gattgcatct ggaccattaa agccactcca aaagcttaag    600
atttatttga ggttcctaga ttatcaaatg gagcactcaa atgaatgcaa gagaaacttc    660
gttgcagtct atgatggaag cagttctatt gaaaacctga aggccaagtt ttgcagcact    720
gtggccaatg atgtaatgct taaaacagga attggagtga ttcgaatgtg ggcagatgaa    780
ggtagtcggc ttagcaggtt tcgaatgctc tttacttcct ttggtggagc ctcccctgca    840
caagcagcac tttccttttg ccatngcaac atgtgcatca ataattcctt aagtcngtaa    900
tggtgtccaa aattgtgcat acccctgggg atn                                 933
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 192
<211> LENGTH: 455
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  192
tttatgtcat caaatattta ttgagtgggc cttctggctg gcatggggcg acacaaatgc     60
cccctgccac catcagagag atcccaggcc ccagggtctt attgccacag tttctgcagt    120
ccattggggg gcggaagtgg ccaggggcat gtgggccggg gtccaggagc agactccagc    180
ctgagtcccc tgtgcccatg gtacccactc tgcccaccag gaaggtgctg caggctggct    240
cctccaggcc ctggcaggag gtgctgaagg acatggtcgg cttagatgcc ttgcatgctc    300
cagccggtgt ctcaagtact tccagccagt cacacattgt gtggaagagc agaaccatca    360
taacggcgag gttgtgctct ggcccgatta ccagttgtga ccgtcgctgc ctgacaacta    420
gccggagggc ataggtaaag ccctgagtga ggatn                               455
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 193
<211> LENGTH: 355
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  193
cgcgtccgct cttacagata ttnacttggt aaatgtgcat gtggggaaga gggaatgcta     60
ngttgatagg gctggtggct tctgaatttg gtatttgaac tacgagtccc tatagagggg    120
ctgctttatg ggaagtnttt ctctgaccag gtacaacacc tgactttaaa ggcctgaaat    180
gctaccattt cttcctctgg ctcaaaattc ttccctgggg agagagttat attcccttat    240
ttattgatat ttagtccaga acaccagttc taacgaagca tgccgtgtct cttcatctac    300
aggatgcaat aggctgattg tatttaaaaa tcaaagtacc caaaactgag tcccn         355
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 194
<211> LENGTH: 461
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  194
tggaggggac caaaaccttg aattttatan agaagtctaa agaaagggga acaagactca     60
taagattgga gaatcatatt tgaatactta aaacaaagct aatgctaaaa agaaactata    120
aatgtctctg gaggcacttc aaagctgtca gccctaatgg cactaagttg cttctataaa    180
atatgtgctt atgtaaaagc aggattttag ttatgggcta agtctaattt cttttctttg    240
gtaatacagt tctctctctc tctctctctc tttctctgtg tgtctgtttt atcaaagcaa    300
tataagcact tgttagaata atgtaatagt taagaagacc ttgccctgtc tttcccatcc    360
caatccccgt ttcttcctcc catcaggcaa ctgctcttaa tatttctatt tttaattttg    420
atagttatct ccacatataa ataatgagct tgtgttccta t                        461
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 195
<211> LENGTH: 570
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  195
tttaccccgc gtccgaatat attgattatt cagaaataga caatacattt tttaattacc     60
caaggactga ctgttttgtg cattttactg ttggttgtct tcagtagaga atagtaatag    120
ggcagagaaa agtatatatt ttgcctcagt cagtcccacc accacaatgg actattggga    180
tattttctaa aaaaccaatc aatttgccca tgattacctc acaaataatt agtgctacct    240
ggggtactct caaatataca gcttttgaaa ctgtagatga aaaaagctct actcagagtt    300
tttgtcaaga ctgtgcctgg gttgaatatc agtcaattgc ctacacttct aaacaataag    360
tgccaatgtc tcaattttct caccctgaat gatagaagct agctttatca aatgccaagg    420
ttagaaagcc tggaaataaa acttaagcac agacattcaa gtttttgaaa agcataagcc    480
taaattcaga taaatcacac tgatatattg tactatgcat agaaagttgt aggtggcgtt    540
cagggaagac tttgatttta ataaagcaat                                     570
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 196
<211> LENGTH: 1149
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: peptidase family m17
<400> SEQUENCE:  196
gatgaacacc gacaccttcc tcgaggagat taacaaagtt ggaaaggagc tggggatcat     60
cccaaccatc atccgggatg aggaactgaa gacgagagga tttggaggaa tctatggggt    120
tggcaaagcc gccctgcatc ccccagccct ggccgtcctc agccacaccc cagatggagc    180
cacgcagacc atcgcctggg tgggcaaagg tcgcgtctat gacactggag gcctcagcat    240
caaagggaag actaccatgc cggggatgaa gcgagactgc gggggtgctg cggccgtcct    300
gggggccttc agagccgcaa tcaagcaggg tttcaaagac aacctccacg ctgtgttctg    360
cttggctgag aactcggtgg ggcccaatgc gacaaggcca gatgacatcc acctgctgta    420
ctcagggaag acggtggaaa tcaacaacac ggatgcccga gggcaggctg gtgctggcag    480
atggcgtgtc ctatgcttgc aaggacctgg gggccgacat catcctgaac atggccacct    540
tgaccggggc tcagggcatt gccacaggga agtaccacgc cgcggtgctc accaacagcg    600
ctgagtggga ggccgcctgt gtgaaggcgg caggaaagtg tggggacctg gtgcacccgc    660
tggtctactg ccccgagctg cacttcagcg agttcacctc agctgtggcg gacatgaaga    720
actcagtggc ggaccgagac aacagcccca gctcctgtgc tggcctcttc atcgcctcac    780
acatcggctt cgactggccc ggagtctggg tccacctgga cattgctgca ccggtgcatg    840
ctggtgagcg agccacaggc ttcggtgtgg ccctccttct ggcgctcttc ggccgtgcct    900
ctgaggaccc tctgctgaac ctggtgtccc cactgggctg tgaggtggat gtcgaggagg    960
gggacgtggg gagggactcc aagagacgca ggcttgtgtg agcctcctgc ctcggccctg   1020
acaaacgggg atcttttacc tcactttgca ctgattaatt ttaagcaatt gaaagattgc   1080
ccttcaaaaa aaaaaaaaaa aaaaaaaaat tccgtgccca gtggtgacag gagtgagcca   1140
ttcttctcn                                                           1149
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 197
<211> LENGTH: 1361
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxy-terminal hydrolases family
2
<400> SEQUENCE:  197
gacccccgtc cntancagcg gaggctggac gcttgcatgg cgcttgagag attccatcgt     60
gcctggctca cataagcgct tcctggaagt gaagtcgtgc tgtcctgaac gcgggccagg    120
cagctgcggc ctgggggttt tggagtgatc acgaatgagc aaggcgtttg ggctcctgag    180
gcaaatctgt cagtccatcc tggctgagtc ctcgcagtcc ccggcagatc ttgaagaaaa    240
gaaggaagaa gacagcaaca tgaagagaga gcagcccacg agagcgtccc agggcctggg    300
actaccctca tggcctggtt ggtttacaca acattggaca gacctgctgc cttaactcct    360
tgattcaggt gttcgtaatg aatgtggact tcaccaggat attgaagagg atcacggtgc    420
ccagggggag ctgacgagca gaggagaagc gtccctttcc agatgcttct gctgctggag    480
aagatgcagg acagccggca gaaagcagtg cggcccctgg agctggccta ctgcctgcag    540
aagtgcaacg tgcccttgtt tgtccaacat gatgctgccc aactgtacct caaactctgg    600
aacctgatta aggaccagat cactgatgtg cacttggtgg agagactgca ggccctgtat    660
acgatccggg tgaaggactc cttgatttgc gttgactgtg ccatggagag tagcagaaac    720
agcagcatgc tcaccctccc actttctctt tttgatgtgg actcaaagcc cctgaagaca    780
ctggaggacg ccctgcactg cttcttccag cccagggagt tatcaagcaa aagcaagtgc    840
ttctgtgaga actgtgggaa gaagacccgt gggaaacagg tcttgaagct gacccatttg    900
ccccagaccc tgacaatcca cctcatgcga ttctccatca ggaattcaca gaccgagaaa    960
gatcttgcca ctcccttgta cttcccccag agcttggatt tcaagccaag atccttccaa   1020
ttgaagcgag agtcttgttg atgcttgagg agcagtctgg agggcagtat gagctttttg   1080
ctgtgattgc gcacgtggga atggcagact ccggtcatta ctgtgtctac atccggaatg   1140
ctgtggatgg aaaatgggtt ctgcttccaa taccccaata cctgctcggt ntcctccgaa   1200
tacacccacc ctactacnna aacccactac cacaccccnc gaanctnnnn nnnnnnnnnn   1260
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn   1320
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn n                       1361
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 198
<211> LENGTH: 502
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  198
cacccccgcg tccgctcaga tcaaggatgt tcaaacgtca agtaattgtg agagttccct     60
gtaatgtaac gaggccttgc aaagattcca atacaaggca gtttcatcct tttgaggcct    120
aacttgggga ggaaatggaa ggagtcatgt tgccctgtgc agagtcatgc atgtgatctg    180
tgttatgata gcaaatggcc agtgttagtt actcttgggg aaagtagtgg gattggatga    240
aggccattgg gggaggccag tgtagcttaa accttttatt taagtatgtg tctgtatggt    300
tttgaaattt ttatattatt ttttaactta gaaataaatg acttaaatat tccctcaaag    360
gcagtcatct gtaggggctt taacaaatat ttgtagtttt ttaaatgtca aagagatggc    420
ttcttactga gatattttcc tgtgtggtga ttttgtttag aaatggagca tctactgttg    480
tcacggctat attcggaggc at                                             502
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 199
<211> LENGTH: 1438
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  199
cgggcaggta cagaaagtca gagaacactt acagaacttg ggaaaaactc agctttcaca     60
gctgacaggc ataagaaaaa agaaaacttt tgggaanaac tccaacacta aacaagcaaa    120
gttattaaaa gtaaatggaa acaaccactg cccatttgtt gccacagggc cttcggaatt    180
tggggaacac atgtttcatg aatgccatcc ttcagtcact cagtaacatt gagcagtttt    240
gctgttattt caaagaactg cccgccgtgg agttaaggaa tgggaaaaca gcaggaaggc    300
ggacatacca caccaggagc caaggggata acaatgtgtc tttggtagaa gagtttagaa    360
agacactctg tgctttatgg caaggcagcc agactgcatt tagcccagag tccttatttt    420
atgttgtttg ggaagattat gccaaacttt agggggctat caacagcagg acgcccatgg    480
aatttcatgg cgctaccttt tgggaccacc tacacttggg aacttcaggg cggtttcaac    540
ggtgtttccc gctcaggcaa tttttgcagg gagaatttct actctgtctg gcaagttaac    600
aagtgttgca taaatggagc atctactgtt ggtcacggct atattcgggg ggcattctcc    660
aaaatgaggt taactgcctc atatgtggga cagaatctag aaagtttgga tccattccta    720
gacctttcat tagatattcc aagtcagttc agaagtaagc gctctaagaa tcaagaaaat    780
ggaccagttt gttcgttacc gagattgtct tcgcagtttt accgacttag gaagaacttg    840
atgagacaga gttatataat gtgccataaa tgcaaaaaga aacaaaagtc cacaaaaaag    900
ttttggattc aaaaactacc caaggtngct atgcttacat ttgaaaagat ttcattggac    960
agcatattta aggaaataaa gttgatacat acgtaggaat ttccactgag aggcctagac   1020
atgaaatgct acttactaga tcctgagaac agtggcccgg agagctgcct gtatgacctc   1080
gccgctgtgg ttgtacacca tggttcccgg ggttggttct ggacattaca cagcatacgc   1140
aactcacgag gcccgctggg tttccacttc aaatgacagt acttgtaaca cttgacttga   1200
ccgaaggaga ctgtgggtga aaggcgaagg ctaaccatcc ctttttctac gttggaacac   1260
caggccaaag ctggatcgga taaactttaa tacctgctgc aaatcatcat tcaccaacca   1320
taccagagaa acatttccag ttttccacaa atacttgata caagatttaa tttcattatg   1380
cacttttcaa tttccctatt tttggattta agttttgtca atggtagtga cttacctg     1438
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 200
<211> LENGTH: 778
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  200
accccgcgtc cgcccagttc ttcatctata aaattgattc atccaaccga gagcagcggc     60
tagaggacaa aggagacacc ccactggagc tgggtgacga ctgtatgcct ggctctcgtc    120
tggcggaaca atgagcgctt gcaggagttt gtgttggtag cctccaagga gctggaatgt    180
gctgaggatc caggctctgc cggtgaggct gcccgggccg gccacttcac cctggaccag    240
tgcctcaacc tcttcacacg gcctgaggtg ctggcacccg aggaggcctg gtactgccca    300
cagtgcaaac agcaccgtga ggcctccaag cagctgttgc tatggcgcct gccaaatgtt    360
ctcatcgtgc agctcaagcg cttctccttt cgtagtttta tcttggcgtg acaagatcaa    420
tgacttggtg gagttccctg ttaggaacct ggacctgaag caagttctgc attggtcaga    480
aagaggagca gctgcccagc tacgatctat atgctgtcat caaccactat ggaggcatga    540
ttggtggcca ctacactgcc tgtgcacgcc tgcccaatga atcgtagcag tcagcgcagt    600
gaccgtgggc tggcgcttgt ttgatgacag cacagtgaca acggtagacg agagccaagg    660
ttgtgacgcc gttatgccta tgtactcttc taccgccggc ggaactctcc tgtggagagg    720
ccccccaggg caggtcactc tgagcaccac ccagacctag gccctgcagc tgaggctg      778
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 201
<211> LENGTH: 693
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  201
ggtttaaaaa caggagacta tttaatccat ctaaaaatac aaatcaggaa aaggggggaa     60
ccataggaaa atcctccacc tctaacagag cgaagttact ggctttctgc ttgctccaag    120
aatcccaagg cttgatgttt ggaaggaatt atctgttctt caactactcc cagatactca    180
agacataagt tacacacatc tggagaaggg ttctgccctg ctgaagctag atgggagctc    240
aatgcatggg agaaaggagc atcaatcatc atcagccaca gcccttggga gcaaagccct    300
agacgcctcc ttcaagcccc ctgctggttg gtttcatcat tatctcgcct cttccaaatc    360
tgaatgtaag cctctgacag tgtgatcatc tggggaagga tgtcagtcac ctggaggtct    420
tggtaattca taccatttgc ctgtcccatg atgaagcacg tggatccggt agagccctcg    480
gagggcttgc cgttcatgca cgatgttggc aatgaggtca taggtggtat tcttgtgtac    540
tgcttgtact tcttcagaca agtattctct cagntccaca tttgtaatan gggaattgac    600
aatagttgga tcttctcaca aagaagttgt cttagtgata tcttgataca aagattggnt    660
tggaggcant tggtnagctg gaggcttcag aat                                 693
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 202
<211> LENGTH: 2276
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  202
gcgctcgagc gtgcttggcg cctgcgctgg acgactcggc cggtaggtgg agatgtccgg     60
ccggtctaag cgggagtctc gcggttccac tcgcgggaag cgagagtctg agtcgcgggg    120
cagctccggt cgccgtcaag cgggagcgag atcgggagcg ggagcctgag gcggcgagct    180
cccggggcag ccctgtgcgc gtgaagcggg agttcgagcc ggcgagcgcg cgcgaggccc    240
cggcttctgt tgtcccgttt gtgcgggtga agcgggagcg cgaggtcgat gaggactcgg    300
agcctgagcg ggaggtgccg agccccacat tggccgagtt ggattcctga ggacccggag    360
gagccgccac tgccccgtac cttggacacc attaacagga attgttgctt ggacttttga    420
ctttgagaaa catgtgttcc tatctccctc tcacacatca atgcttatgc ctgtctggtg    480
tgtggcaagt actttcaagg ccggggtttg aaagtctcac gcctacattc acagtgtcca    540
gtttagccac catgttttcc tcaacctcca caccctcaag ttttactgcc ttccagacaa    600
ctatgagatc atcgattcct cattggagga tatcacgtat gttttgaagc ccactttcac    660
aaagcagcaa attgcaaact tggacaagca agccaaattg tcccgggcat atgatggtac    720
cacttacctg ccgggtattg tgggactgaa taacataaag gccaatgatt atgccaacgc    780
tgtccttcag gctctatcta atgttcctcc tctccggaac tactttctgg aagaagacaa    840
ttataagaac atcaaacgtc ctccaggggg atatcattgt tcttgttggt ccagcgtttt    900
ggagagctga tgagaaagct ctggaaccct cgaaatttca aggcacatgt gtctccccat    960
gagatgcttc aggcagttgt actttgcagt aagaagactt ttcagatcac caaacaagga   1020
gatgggcgtt gactttctgt cttggtttct gaatgctctg cactcagctc tggggggcac   1080
aaagaagaaa aagaagacta ttgtgactga tgttttccag gggtccatga ggatcttcac   1140
taaaaagctt ccccatcctg atctgccagc agaagaaaaa gagcagttgc tccataatga   1200
cgagtaccag gagacaatgg tggagtccac ttttatgtac ctgacgctgg accttcctac   1260
tgcccccctc tacaaggacg agaaggaagc agctcatcat ttccccaagt gccactcttc   1320
aacatcctgg gctaagttca atgggcatca cttgagaagg aatataagac ttacaaggag   1380
aactttctga agcgcttcca gcttaccaag gttgccttcc atatctaaat cttttgtatc   1440
aagagattca ctaaggaaca acttctttgt tgaggaagga atccaactat ttgtcaattt   1500
ccctattaca aatgtggatc tgagagaata cttgtctgaa gaagtacaag cagtacacaa   1560
gaataccacc tatgacctca ttaccaacat cgtgcatgac ggcatgccct ccgaggttcg   1620
ctaccggtat ccacgttgct tcatcatggt tacaggcaaa tggttatgaa ttacaagacc   1680
ttccaggtga ctgacatcct tccccagatg atcacactgt cagaggctta catgtcagat   1740
ttggaagagg cgagataatg atgaaaccaa ccagcagggg gcttgaagga ggcgtctagg   1800
ggctttgctc ccaagggctg tggctgatgg atggtaaata agaacacaga agctgtagct   1860
gaacacaggt gggctggtgg gcttcctagg gccagcccag cttgtatggg gttctggcta   1920
caccagagca ccaagagccc acttgcctgg gatggcccca cactgtcact cagctgttct   1980
ttgatcattt ttttctagat tgatgctcct ttctcccatg cattgagctc ccatctagct   2040
tcagcagggc agaacccttc tccagatgtg tgtaacttat gtctgagtat ctgggagtag   2100
ttgaagaaca gataattcct tccaaacatc aagccttggg attcttggag caagcagaaa   2160
gccagtaact tcgctctgtt agaggtggag gattttccta tggttccccc catttcctga   2220
tttgtatttt tagatggatt aaatagtctc ctgtttttaa aaaaaaaaaa aaaagg       2276
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 203
<211> LENGTH: 503
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  203
tttttttttt tttttttgta atcaaattta cttttattca caaattattt tttcaaacat     60
ttactacatt gaaataaaaa tttatcaaca aaatattaaa atctggttta taattttgat    120
ttttaaagtg aggaaaattc taccttggca gtgaagacag cctgtcttgc ctcaggtatc    180
atataaagtt gctgaatagt agaagctaag taacaagtag ctccaaggtt agtaaggcca    240
acaaatctac attcagcacg gacatcttca tgaggccagt aatcccattt ataaggtgca    300
tgggactgca tgtgttgtgc cataacccag ttgtgtatta gcctgtagtt ctcaacagac    360
ccctttacca tctctactaa caaatcgtaa gcggcagctc ttgaagaatg tgatttgcac    420
tttggctgtt gtcggtcctt tagacttggc aacaaaaaca ggagattgaa gatatctctc    480
aaaaattcct gtcccggggc ggg                                            503
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 204
<211> LENGTH: 507
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  204
gaaagttgtt tacatcgctg gaggacagaa atagaaaatg acaccagaga tttgcaggaa     60
agcatatcca gaatccatcc gaacaattga attaatgtac tctgacaaat ctatgataca    120
agttccttat cgattacatg ccgttttagt tcacgaaggc caagctaatg ctgggcacta    180
ctgggcatat atttttgatc atcgtgaaag cagatggatg aaagtacaat gatattgctg    240
tgacaaaatc catcatggga agagctagtg agggactctt ttggtggtta taagaaatgc    300
cagtgcatac tgtttaatgt acataaatga taaggcacag ttcctaatac aagaggagtt    360
taataaagaa actgggcagc ccccttgttg gtatagaaac attaccaccg gatttgagag    420
attttgttga ggaagacaac caacgatttg aaaaagaact agaagaatgg gatgcacaac    480
ttgcccagaa agctttgcag gaaaagc                                        507
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 205
<211> LENGTH: 576
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  205
ccgcggacag tctcaacaat gacaacaagt attccctgtt tgctgttgtt aaccatcaag     60
ggaccttgga gagtggccac tacaccagct ttatccggca gcacaaagac cagtggttca    120
agtgtgacga tgccatcatc accaaggcca gcatcaagga cgtcctggac agcgaagggt    180
acttgctgtt ctatcacaaa cagttcctgg aatacgagta gccttatctg cagctggtca    240
gaaaaacaaa ggcaatgcat tggcaagcct cacagcacag agtgaccgct acctgctgta    300
agattatggg tccatgaaag cagtaagctg gacacagagg tgtagtgtgc gggacagagg    360
gccttgcaga tgcctttctg ttggtgtttt agtgttaaaa tacggagagt atggaactct    420
tcacctccat tttctcagcg gctgtgaagc agcctcctag cttcggaagt acggacacta    480
cgtcgcgttt tcaagcgtgt ctgttctgca ggtaacagca ttcaagctgc acgtggaagc    540
atttcgcggg ttttctagaa acaggcattt tcttat                              576
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 206
<211> LENGTH: 424
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  206
tccgcagaaa tttaggtaac ttctccttta gtctcaagag cgagtcttgc tttttaatgg     60
gtgccgttta tgttgctgcc cgccctgtgt gcctggctcc tctgggtgcc ttggtgtctg    120
ctggtggctg gcagtgggcg cagcggagga gagttgtgct gcagctcata cggtgtgtct    180
gtcatctcag tctggagtaa atgcagtgtc tgccggtgtc tgatgggttc tgtccctcgt    240
attttctttg ccttctatcc ctgcctggca gccaagggtg ttggtcgcga agctggagtg    300
gcctctggtg gagcctgcat cttgtctcgt ctgcctctgc tttacatttg gtgtactttc    360
gggcgtggtg ggcagtaaaa tgacaccgtg attgagcttg tcagcagagc tgaaagagaa    420
agta                                                                 424
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 207
<211> LENGTH: 1465
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  207
ctagtttact ctggacaccg gtcccctcac atcccgtata acgttgctgc acctggtgtg     60
gacccacgcg aggcacctag caggctacga gcagcaggac gcccacgagt tcctcatcgc    120
ggccctggac gtgctccacc gacactgcaa aggtgatgac aatgggaaga aggccaacaa    180
ccccaaccac tgcaactgca tcatagacca cgatcttcac aggcgggttg cagtcagacg    240
tcacctgcca agtctgccat ggagtctcca ccaccatcga ccccttctgg gacatcagct    300
tggatctccc cggctcttcc accccattct ggcccctgag cccagggagc gagggcaacc    360
gtggtaaacg gggaaagcca ccgtgtcggg aaccaccacg ctcacggact gcctgcgacg    420
attcaccaga ccagagcact tgggcagcag cgccaagatc aagtgcagcg gttgccatag    480
ctaccaggag tccacaaagc agctcactat gaagaaactg cccatagtag cctgttttca    540
tctcaaacga tttgaacact cagccaagct gcggcggaag atcaccacgt atgtgtcctt    600
ccccctggag ctggacatga cccctttcat ggcctccagc aaagagagca ggatgaatgg    660
acagtaccag cagcccacgg acagtctcaa caatgacaac aagtattccc tgtttgctgt    720
tgttaaccat caagggacct tggagagtgg ccactacacc agctttatcc ggcagcacaa    780
agaccagtgg ttcaagtgtg acgatgccat catcaccaag gccagtatta aggaccgtac    840
tggacagcga aagggtactt gctgttctat cacaaacagt tcctggaata cgagtagcct    900
tatctgcagc tggtcagaaa aacaaaggca atgcattggc aagcctcaca aagtgatcct    960
ccctggccac ccccctcccc caagcctccc gccgcctccc cggcctggtg acaccacctc   1020
ccatgcagat gtggcccctc tgcacctggg acccatcggg tcgggatgga ccacacggac   1080
ggggaggctc ctggagcttg ctttgaagat ggatgagatg aggggtgtgc tctgggtggg   1140
aggagcaagc gtacaccccg tcaccagaac atctccttgt gtcatgacat gggggtgcaa   1200
cgggggcctc acagcacaga gtgaccgctg cctggcgttc cccagcactc ggtgtggaaa   1260
ggcccctacc tgctgtaaga ttatgggtcc atgaaagcag taagctggac acagaggtgt   1320
agtgtgcggg acaaaagggc cttgcagatg cctttctgtt ggtgttttag tgttaaaata   1380
cggagagtat ggaactcttc acctccattt tctcagcggc tgtgaagcag cctcctagct   1440
tcggaagtac ctcggccgcg accac                                         1465
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 208
<211> LENGTH: 492
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  208
ggaaccacgc gtccgtcccg cgtccgcttt taattaggga acaaatctaa tggaaagacc     60
actcataggc caggtgcggt ggctcacgcc tataatccca gcnctttggg acgctgaggt    120
gggtggatcg cctgaggtca ggagtttgag acatggccaa acccaggcag ctgccagaaa    180
gccttctgca ctccgcaaga caccccagta aactggggcg tcccaaggtg gcaagccttc    240
atgaaggcac tgcccagctc acaatcctgt gggccaactt cagtcaactc tcctttccat    300
tagatttgtt cctaattaaa agaccactca taggccaggt gcggtggctc acgcctataa    360
tcccagcact ttgggacgct tgaggtgggt ggatcgcctg aggtcaggag tttgagacat    420
ggtgaaaccc catctctact aaaaatacaa aaattagcct ggcgtggtgg cgcatgcctg    480
tagtcccagc ta                                                        492
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 209
<211> LENGTH: 470
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  209
gctttgaaca caatctggcc ttcagatgca gttgagacat tacagtaatc atcaaaataa     60
tcccatctcc accatgctta ttttgcaaaa gcagtatagg gccttcctct catccctcca    120
tagtggttgg aaacagcaat caaattatag cagcgaggcc ctgcgcttgg attaatcaga    180
aattccaata cagccaagtc attgatagga aaatcaacta agttatctaa cttgtttctc    240
aaggatctac tgtaaggaaa aatcacttga ggatgcaaca gctactggga gggcagggat    300
catacatcca atttcttagt ggtggctgct tcttggacgg atttgggata ccnggggatc    360
ttttatccac ttaggttttc ctttttgttt gnaaaagggg tcntgagggc cgtctttttt    420
aattttcggc aaaaggtttt tttttttttt tccaggggag gtttatattn               470
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 210
<211> LENGTH: 2786
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  210
tttttttttt tagggtaagt cagtttattg atgtgttgtg atccatcacc cagatatatt     60
aaacacaaag tacttaagta attcaggatt tcctttccag aaacaaagca ggaataaaaa    120
ccactatgac aatataaaac ctttgtacat ttttaggtat ttttcccttc aatatttaaa    180
taaacatgat ttcttctggc atgtatttaa tgttaagtga acatgatttt aattagtctt    240
tttttatcgt tatttcagcc attataaaag ccataaatgt gtttccagaa aaagtgcttt    300
tgatattatt acagtattct ctcataaaat aggaggtacg cttgtgagtt tagtacttta    360
gttgtaggca cagcttgcac atgtgtgtcg ctgatgtgaa accactggcc cttttgattc    420
catttcaaaa tcttgtggaa tatcaccgtg aaagaacaag attagagaga tgactatttg    480
cgggttcttg ccttggcata gggcagtgta atgccccgac ctcatagtac cacgtgtgtt    540
caacaaactc catataagga atagagtacc cttgtatttt cttctgcaac attcttacat    600
ttaagggtgc aaaaaggagc caaatctaag atttccggaa aactttatgt gtttgttaac    660
cttgcgtagg taaaaaccag cctgctgaaa tctctttaaa tgaagagtaa gaacaggagg    720
agcaagagaa attagcatct gctttttggc attggtgtaa acatgcttcc tttcaccttt    780
tatatttgcc tttggtccat tacactgtct ccgtgtgcat acttcacaaa gcagtttatt    840
cgcatctcga agtttctcat tacgggtgaa ctgatataaa caatgttgga ttgaacactc    900
atcagtattg aaaacttccc tgtttgcaag agtacagaaa gcagtttctg gatcttcatt    960
tacaacctca tacacctttg ttccaggagt atgactatca ttcagaatct ctatatttat   1020
ttcatcagga tgaagagcag cattcaaatt taggtttttg aaaccattgg aaatgtccac   1080
ttctccattg ctcccttccg ttaggtaggc accatttaaa ttcctagtgg gagaagatgt   1140
taaaacctcc cagatcatta tccatgttga tatttttcat atctacttcc ctctgtggat   1200
ttttgattgt cagttacact ttcggatcat ttttgcttgg ccattcaaat ctttctggtt   1260
gacacaatat tctttatgca taacaccctc ttgtgaaata tggttggatt taatatttaa   1320
cttctccttg aagtgacatt tcagcttcat attcactgtc ttcaggatgg tcaatagtac   1380
aaatatcatt taaatgaaga acttttcctt gaattttttg ttgtcttcgt tggttcttgg   1440
cttgcttttt ggcttgtttc tttgcttttt tctgtaagtg cttacgttgt tccagaagga   1500
atatcacttc tctcttttat gtaactgtcg ttatcttttt cttcctcact atcttgatct   1560
tcatcctcca cgtgtctttt tcagattttt atcatttaca cttttcttac cactctgatc   1620
atctaaaact gggagggaca aatcaaggaa agattcatga accaaggaga cagttctgca   1680
ttgatcacac atgatcatac tagttagttc accaccaaag atgcggtcgg acaaaacttg   1740
gcattgattt tttcttctca taatcgttta acgtttattt tttagttctt catccaactt   1800
ttcagtagaa ttaccaaatg ctttaagtat tcctttactc actctttggt gttcttctgc   1860
tctcatccca tccaataagt agcgaagcag ctcctggctg tcttgctgct gatagccttt   1920
aaaccgcact gcttttttac agacctgaga aaagagttct ttcggtgtca caaccccctt   1980
tttggtctct tgcatctcat taagaaactg gctcatggct aaagtaagag ggcctggagg   2040
ctcaaggttt atttctaatg gttctgttaa tgccaaatca ggtggttcaa tttttacaat   2100
tgttccagac attttcactt cttttagtag ttctctaagc actggtgttt gtgacaagtt   2160
ctgcataact gcattgaaga aacatgtgtt tcccaaatta ctgagtcctt tcncggttat   2220
ttggcaagga gaattcatgg gaggattctc tttagccatg ttttccttct tttctctctc   2280
ttgttcattc ttactctctt tttctaattt tccattttca agttcaatat ttccattatc   2340
tttctctgct ggctttggag ttgtaatgct ggcttgtttt ctgacataat caaccacttg   2400
acccaactgg tttgaactac aatactggac ctcattatca catacgtaac accatacact   2460
ccagttgtcc aaactaagaa ccagacagtg aggttcagat cttggcgtca gatagtgctt   2520
caaggcatgc tgctcctgag aatttctgcc acagccctga tggccacatt taagacacag   2580
ccaaactgaa ggcttttctt ctgtttcttc ttcagcttta tctttcactt tattgtcagt   2640
cttacagtct tggcagatat tccattccac attcactaaa gcctttttca aattaccttg   2700
ttccaatcct tttctaatgt gtctgcacac aggttctaaa gtttcagagg aatcatcgat   2760
tggaacagtt tttccctttg tccgtt                                        2786
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 211
<211> LENGTH: 805
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  211
tttttaaagt taactatttt aattagaatt tgtattctaa caggataaaa taactacatt     60
tagcttgccc tttccagtgg acgcttttgc ccaaatgtca gctaacaagg agtccatctc    120
cttccccacc caagctgtct agcagccaga gtggtagctt tactgtaaca cacagtactt    180
tttgtaatca gactcaaagt cttcatccat actgcttgtg tctgccatct ttttgccatc    240
agtctttggc agaaattgtg catagtctat cccctgctgc tcatagaaaa agaatgtagg    300
cagagtcggt gtcaatttca tcccgggtga gttcctttac agctgctgtc attgtaacag    360
taccacttgc agtttggggt ttttgggcat aagtgacgta atgggccccc acccaggatt    420
ccccgaatgg gcacggaaat tggcatatag gtttttaaat agggttaata cgggtatctt    480
ctctttgggg catcagtgct gtcttcttca ctgtgggttt ccaggttgac cattgctgta    540
gccattgcca catgcttcat gctcataaat gaatccattg gccaaagcct acctcatggt    600
cctgaggagt gaccaactct ggttggctgc cccccagcac atgccctcga ctcaagcgtc    660
agccagctca catatctgcc cagccccatt ttctttgctg gcatccaagt tctctttact    720
acttgacagt ttatttttgc tgccaatctg gggcagccgg agcctccctt tgctcctcnc    780
caaagtccgt gggctgctaa ttagg                                          805
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 212
<211> LENGTH: 1072
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  212
caggaggcgg accccccgag ggcagcgctg cggggccgtt ttccggccct cctgacgcga     60
cactgcccct ctccgagagc tgagaaggaa aagaggagct tgcggaggtg cggctgcagg    120
ccgttgttgg tcgagctggc gggtcccgcg ggccaggccg tggaggtgtt acctcatttt    180
gaaagtcttg ggaaacagga aaaaattcct aacaaaatgt cagcttttcg aaatcattgt    240
ccacatttgg gattcaagtt gggtgaaata acaaaagaag atttgataca aaaatccctt    300
ggtacttgtc agggattgta aagtccaagg accaaatctt tgggcatgtc tggagaatag    360
atgttcatat gttggctgtg gtgaatcaca agtagatcac agcaccatac attctcagga    420
gacaaagcat tatctaactg tgaaccttac cactcttcga gtatggtgtt atgcttgcag    480
caaagaagta ttttttggat aggaaattag gaactcagcc ttcattgcct catgtaagac    540
aacctcacca aatacaagaa aacagtgtcc aggattttaa aatacccagt aatacaacat    600
taaaaactcc tctggttgcc gtatttgatg atctggatat agaagcggat gaagaagatg    660
aacttagggc aagaggtctt acaggtttga aaaatattgg aaatacttgt tacatgaatg    720
cagctttgca ggctctttct aattgcccac ctttgacaca gttttttctt gattgtggag    780
gactagctcg aacagataag aaacctgcca tttgtaaaag ttatctcaaa ctaatgacag    840
agctgtggca taaaagcagg ccaggatctg ttgtgcctac tactctgttt caaggaatta    900
aaactgtaaa tccaacattt cgggggtatt ctcagcagga tgctcaagaa ttccttcnat    960
gtttaatgga tttgcttcat gaagaattga aagagcaagt catggaagta gaagaagatc   1020
cgcaaaccat aaccactgag gagacaatgg aagaagacaa gagccagtcg ga           1072
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 213
<211> LENGTH: 465
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  213
gtccgcactg tatgatgtat cattattctg gatttccaga tctctatgaa cctattctgg     60
aggcaataaa ggattttcct aagcccagtg aagagaagat taagttaatt ctcaatcaaa    120
gtgcctggac ttctcaatcc aattctttgg cgtcttgctt gtctagactt tctggaaaat    180
ctgaaactgg gaaaactggt cttattaacc taggaaatac catgttatat gaacagtgtt    240
atacaagcct tgtttatggc cacagatttc aggagacaag tattatcttt aaatctaaat    300
ggggtgcaat tcattaatga aaaaattaca gcatcttttt gcctttctgg cccatacaca    360
gagggaaagc catacgcacc tccggatatt cctttggagg cttcccagac ctcccatggt    420
ttactcccca gattcaccag ccaagactgt tcctgaaata cctcc                    465
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 214
<211> LENGTH: 457
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  214
atggagcgag cgccgagccg ggtcagagtt gaacaatgac catagttgac aaagcttctg     60
aatcttcaga cccatcagcc ttatcatgaa tcagcctggc atctccgagg cagtctcacc    120
tggagacatg gatgcaggtt ctgccagctg gggtgctgtg tcttcattga atgatgtgtc    180
aaatcacaca ctttctttag gaccagtacc tggtgctgta gtttattcga gttcatctgt    240
acctgataaa tcaaaaccat caccacaaaa ggatcaagcc ctaggtgatg gcatcgctcc    300
tccacaggaa agtacttttc ccatctgaga agatttgtct taagtggcaa caaactcata    360
gagttggagc tgggctccag aaatttgggg caatacctgg ttttgccaat gcagcactgc    420
agtgtttaac ctacacacca cctcttgcca attacat                             457
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 215
<211> LENGTH: 165
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  215
gtccgattac ctaaagcgct ttcggcacga ggtgatgtac tcattcaaga tcaacagcca     60
cgtctccttc cccctcgagg ggctcgacct gcgccccttc cttgccaagg agtgcacatc    120
ccagatcacc acctacgacc tcctctcggt catctgccac cacgg                    165
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 216
<211> LENGTH: 460
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  216
gcacaacttg accgtgaacc tgacccgttc cgactgtggt gttacgcctg tgagaaggag     60
gtattcctgg agcagcggct ggcagcccct ctgctgggct cctcttccaa gttctctgaa    120
caggactccc cgccaccctc ccaccctctg aaagctgttc ctattgctgt ggctgatgaa    180
ggagagtctg agtcagagga cgatgacctg aaacctcgag gcctcacggg catgaagaac    240
ctcgggaact cctgctacat gaacgctgcc ctgcaggccc tgtccaattg cccgccgctg    300
actcagttct tcttggagtg tggcggcctg gtgcgcacag ataagaagcc agccctgtgc    360
aagagctacc agaagctggt ctctgaggtc tggcataaga aacggccaag ctacgtggtc    420
cccaccagtc tgtctcatgg gatcaagttg gtcaacccaa                          460
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 217
<211> LENGTH: 672
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  217
ggcgcgcccg cggagacgcc ggggctctga cgcccgctct gcggcttcgg tgtttgaaca     60
ggccacagtc caggagcgct tacattcagg agctccgcgt agcacctgcc caaccaaact    120
cagccctccg ttaagatcct ggttccatgc cgcagtagga cagcaggccc aagtctgcac    180
atcccaggca gtgagcacac gtatgagagc tgtggtgacg gagtcccagc cccgcagaaa    240
gtgcttttcc ccacggagcg actgtctctg aggtgggagc gggtcttccg cgtgggcgca    300
ggactccaca accttggcaa cacctgcttt ctcaatgcca ccatccagtg cttgacctac    360
acaccacctc tagccaacta cctgctctcc aaggagcatg ctcgcagctg ccaccaggga    420
agcttctgca tgctgtgtgt catgcagaac cacattgtcc aggccttcgc caacagcggc    480
aacgccatca agcccgtctc cttcatccga naactgaaaa agatcgcccg acacttccgc    540
tttgggaacc aagaagangc gcatgaattc ctgcggtaca ccatcgacnc catgcaaaaa    600
ncctgcctga atggctgtgc caagttggat cttcaaacnn agctactaac tttggtccat    660
caaatttttg ga                                                        672
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 218
<211> LENGTH: 612
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  218
tccggcgtcg cggtgacacg tgtgtgaggc gccggaggcc cggatggtgc gcgtgctggg     60
ccgcgggccg aaggagtcgc cagggctgcg taggcttgtg gcgcgcccgc ggagaggccg    120
gggctctgac gcccgctctg cggcttcggt gtttgaacag gccacagtcc aggagcgctt    180
acattcagga gctccgcgta gcacctgccc aaccaaactc agccctccgt taagatcctg    240
gttccatgcc gcagtaggac agcaggccca agtctgcaca tcccagtgat gcaccatgcc    300
aatagtggat aagttgaagg aggctcctga aacccggccg caaggactcg gctgatgatg    360
gagaactggg gaagcttctt gcctcctctg ccaagaaggt ccttttacag aaaatcgagt    420
tcgagccagc cagcaagagc ttctcctacc agctggaggc cttaaagagc aaatatgtgt    480
tgctcaaccc caaaacagag ggagctagtc gccaccaaga gtggagatga cccaccggcc    540
aggagacagg gcagtgagca cacgtatgag agcttgtggt gacggagtcc cagccccgca    600
gaaagtgctt tt                                                        612
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 219
<211> LENGTH: 917
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  219
ctgcccaggg aagcttctgc atgctgtgtg tcatgcagaa ccacattgtc caggccttcg     60
ccaacagcgg caacgccatc aagcccgtct ccttcatccg agacctgaaa aagatcgccc    120
gacacttccg ctttgggaac caggaggacg cgcatgagtt cctgcggtac accatcgacg    180
ccatgcagaa agcctgcctg aatggctgtg ccaagttgga tcgtcaaacg caggctacta    240
ccttggtcca tcaaattttt ggagggtatc tcagatcacg cgtgaagtgc tccgtgtgca    300
agagcgtctc ggacacctac gacccctact tggacatcgc gctggagatc cggcaagctg    360
cgaatattgt gcgtgctctg gaactttttg tgaaagcaga tgtcctgagt ggagagaatg    420
cctacatgtg tgctaaatgc aagaagaagg gtccagccag caaagcgctt caccattcac    480
agaacattca acgtcttaac cctttccctc aagcgctttg ccaacttcag cggggggaag    540
atcaccaagg atgtaggcta tccggaattc ctcaacatac gtccgtatat gtcccagaat    600
aatggtgatc ctgtcatgta tggactctat gctgtcctgg tgcactcggg ctacagctgc    660
catgccgggc actattactg ctacgtgaag gcaagcaatg gacagtggta ccagatgaat    720
gattccttgg tccattccag caacgtcaag gtggttctga accagcaggc ctacgtgctg    780
ttctatctgc gaattccagg ctctaagaaa agtcccgagg gcctcatctc caggacaggc    840
tcctcctccc ttcccggccg ccgagtgtga ttccagatca ctccaagaag aacatcggca    900
atgggattat ttcctcc                                                   917
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 220
<211> LENGTH: 668
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  220
ccccgcgtcc gcggacgcgt gggcgaaact gcaaaggaaa tcccgaattg cttggttggt     60
attggtgagc atatttggtt aggagaaata gatgaaaata gttttcataa catcgatgat    120
cccaactgtg agaggagaaa aaagaactca tttgtgggcc tgactaacct tggagccact    180
tgttatgtca acacatttct tcaagtgtgg tttctcaact tggagcttcg gcaggcactc    240
tacttatgtc caagcacttg tagtgactac atgctgggag acggcatcca agaagaaaaa    300
gattatgagc ctcaaacaat ttgtgagcat ctccagtact tgtttgcctt gttgcaaaac    360
agtaataggc gatacattga tccatcagga tttgttaaag ccttgggcct ggacactgga    420
caacagcagg atgctcaaga attttcaaag ctctttatgt ctctattgga agatactttg    480
tctaaacaaa agaatccaga tgtgcgcaat attgttcaac agcagttctg tggagaatat    540
gcctatgtaa ctgtttgcaa ccagtgtggc agagagtcta agcttttgtc aaaattttat    600
gagctggagt taaatatcca aggccacaaa cagttaacag attgtatctc ggaatttttg    660
aagggaga                                                             668
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 221
<211> LENGTH: 525
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-termianl hydrolases
family 2
<400> SEQUENCE:  221
cgcgtccgcg gacgcgtggg cgccctcgcc aacatggcgg cgcccagttg gggcgggttc     60
gttcgcttcg cgttttggcc agggcggggg tctgggcttt aggcaggtag tatttagttt    120
cacaatgttt ggggacctgt ttgaagagga gtattccact gtgtctaata atcagtatgg    180
aaaagggaag aaattaaaga ctaaagcttt gtaagccacc tgctcctaga gaattcacca    240
atttaagcgg aatcaagaaa tcagggtgga acctgttacc tcaattccct tcttcagact    300
cttcatttca cacctgaatt cagagaagct ctattttctc ttggcccaga agagcttggt    360
ttgtttgaag ataaggataa acccgatgca aaggttcgaa tcatcccttt acagttacag    420
cgcttgtttg ctcagcttct gctcttagac caggaagctg catccacagc agacctcact    480
gacagctttg ggtggaccag taatgaggaa atgaggcaac atgat                    525
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 222
<211> LENGTH: 1998
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  222
tttaccaagt gcagtctctc tttggacatt taatggaaag caagctgcag tactatgtac     60
ctgagaattt ttggaagatt ttcaagatgt ggaataaaga actttatgtg agagaacagc    120
aggatgcata tgaattcttt actagtctca ttgatcagat ggatgaatac ctcaagaaaa    180
tggggagaga ccaaattttt aagaatacat ttcagggcat ctactctgat cagaagatct    240
gtaaagactg tcctcacaga tatgagcgtg aagaagcttt catggctctc aatctaggag    300
tgacttcttg tcagagtttg gaaatttctt tggaccaatt tgttagagga gaagttctag    360
aaggaagtaa tgcgtactac tgtgaaaagt gtaaagaaaa gagaataaca gtgaaaagga    420
cctgtattaa atctttacct agcgtcttgg taattcacct aatgagattt gggtttgact    480
gggaaagcgg acgctccatt aaatatgatg aacaaataag gtttccctgg atgctaaaca    540
tggagcctta cacagtttca ggaatggctc gccaagattc ttcttctgaa gttggggaaa    600
atgggcgaag tgtggatcag ggcggtggag gatccccacg aaaaaaggtt gccctcatag    660
aaaactatga acttgtcggt gtcatcgtac acagtgggca ggcacacgca ggccactact    720
attccttcat taaggacagg cgagggtgtg gaaaaggaaa gtggtataaa tttaatgaca    780
cagttataga agaatttgac ctaaatgacg agaccctgga gtatgaatgc tttggaggag    840
aatatagacc aaaagtttat gatcaaacaa acccatacac tgatgtgcgc cgaagatact    900
ggaatgccta tatgcttttc taccaaaggg tgtctgatca gaactcccca gtattaccaa    960
agaaaagtcg agtcagccgt tgtacggcag gaagctgagg atctctctct gtcagctcca   1020
tcttcaccag aaatttcacc tcagtcatcc cctcggcccc ataggccgaa caatgaccgg   1080
ctgtctattc ttaccaagct ggttaaaaaa ggcgagaaga aaggactgtt tgtggagaaa   1140
atgcctgctc gaatatacca gatggtgaga gatgagaacc tcaagtttat gaagaataga   1200
gatgtataca gtagtgatta tttcagtttt gttttgtctt tagcttcatt gaatgctact   1260
aaattaaagc atccatatta tccttgcatg gcaaaggtga gcttacagct tgctattcaa   1320
ttcctttttc aaacttatct acggacaaag aagaaactca agggttgata ctgaagaatg   1380
gattgctacc attgaagcat tgctttcaaa aagttttgat gcttgtcagt ggttagttga   1440
atattttatt agttctgaag gaccgagaat tgataaagat tttcttactg gagtgcaatg   1500
tgagagaagt acgagttgct gtggccacca ttctggagaa aaccctagac agtgccttgt   1560
tttatcagga taagttaaaa agccttcatc agttactgga ggtactactt gctctgttgg   1620
acaaagacgt cccagaaaat tgtaaaaact gtgctcagta ctttttcctg ttcaacactt   1680
ttgtacaaaa gcaaggaatt agggctggag atcttcttct gaggcattca gctctgcggc   1740
acatgatcag cttcctccta ggggccagtc ggcaaaacaa tcagataccg tcgatggagt   1800
tcagcacaag cacgagaatt tgggaatctt cacaatacag tggcgttact tgttttgcat   1860
tcagatgtct catcccaaag gaatgttgct cctggcatat ttaagcaacg accacccatt   1920
agcattgctc cctcaagccc tctgttgccc tcatgaggag gtagaagcct tgtgttcatg   1980
tctgaaggga aaccttan                                                 1998
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 223
<211> LENGTH: 722
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  223
ggtgttctgt gggtctcccc tcctgggaag ctctaagtac cctctacctg aatatgtgga     60
atgatctgtg ccctcggaaa tgtttctcct gtttccattt ccttctagga tgtgaaatac    120
cctgagtatc ttgatattcg gccatatatg tctcaaccca acggagagcc aattgtctac    180
gtcttgtatg cagtgctggt ccacactggt tttaattgcc atgctggcca ttacttctgc    240
tacataaaag ctagcaatgg cctctggtat caaatgaatg actccattgt atctaccagt    300
gatattagat cggtactcag ccaacaagcc tatgtgctct tttatatcag gtcccatgat    360
gtgaaaaatg gaggtgaact tactcatccc acccatagcc ccggccagtc ctctccccgc    420
cccgtcatca gtcagcgggt tgtcaccaac aaacaggctg cgcaggcttt atcggaccac    480
agcttccctc tcacatgata aagaatccac ctcacttaaa tgggacatgg accattgaaa    540
gacacgccaa gcagttccat gtcgagtcct aacgggaatt ccagtgtcaa cagggctagc    600
ctgttaatgt tcactntgtc caaaatggtc agttaatagg tctcagtgat ccagaacatc    660
tangaaacaa aaaattcaan agtatnacaa caagttgctg tcgcagtgta gntacanacc    720
tt                                                                   722
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 224
<211> LENGTH: 576
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  224
ccgggtgaag ctcaggaatc tgattgagcc agagcagtgc accttctgtt tcacggcttc     60
tcgcatcgac atctgccttc gtaagaggca gagtcagcgc tgggggggcc tggaggcccc    120
ggctgcacga ggtgcagtgg gtggtgcaaa ggttgccgtg ccgacaggtc caacccctct    180
ggattcaacc ccaccaggag gtgctcccca ccccctgaca ggccaggagg aggcccgggc    240
tgtggagaag gataaatcca aggcacgatc tgaggacaca tgggctagac agtgtggcaa    300
cccgcacacc catggagcat gtaaccccaa agccagagac acacctggcc tcgcccaagc    360
ctacatgcat ggtgcctccc atgccccaca gcccagttag tggagacagc gtggaggagg    420
aggaagagga agagaagaag gtgtgtctgc caggcttcac tggccttgtc aatttaggca    480
acacctgctt catgaacagc gtcattcagt ctctgtccaa cactcgggaa ctccgggact    540
tcttccatga ccgctccttt gaggctgaga tcaacc                              576
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 225
<211> LENGTH: 825
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  225
tggaaggtga taacatgtat acttgttctc attgtgggaa cgaaagtacg agctgaaaaa     60
agggcatgtt ttaagaaatt gcctcgcatt ttgagtttca atactatgag atacacattt    120
aatatggtca cgatgatgaa agagaaagtg aatacacact tttccttccc attaccgttt    180
ggacatgacg ccctatacag aagattttct tatgggaaag agtgagagga aagaaggttt    240
taaagaagtc agtgatcatt caaaagactc agagagctat gaatatgact tgataggagt    300
gactgttcac acaggaacgg cagatggtgg acactattat agctttatca gagatatagt    360
aaatccccat gcttataaaa acaataaatg gtatcttttt aatgatgctg aggtaaaacc    420
ttttgattct gctcaacttg catctgaatg ttttggtgga gagatgaccg accaagacct    480
atgattctgt tacagataaa tttatggact tctcttttga aaagacacac agtgcatata    540
tgctgtttta caaacgcatg gaaccagagg aagaaaatgg cagagaatac aaatttgatg    600
tttcgtcaga gttactagag tggatttggc atgataacat gcagtttctt caagacaaaa    660
acatttttga acatacatat tttggattta tgtggcaatt gtgtagttgt attcccagta    720
cattaccaga tcctaaagct gtgtccttaa tgacagcaaa gttaagcact tcctttgtcc    780
tagagacatt tattccattc taaagaaaag cccacgatgc ttcag                    825
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 226
<211> LENGTH: 147
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  226
atgaactcag cgcagtcctc atacacagag gagttgagta gcttattctg gccactacat     60
cgcccacgtg aaagatccac agtctggtga atggtataag tttaatgatg aagacataga    120
aaagatggag gggaagaaat tacaact                                        147
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 227
<211> LENGTH: 1719
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  227
ccttttctga agataataat gaaacaacaa tgttaattca ggatgatgaa aacaattcag     60
aaatgtcaaa ggattggcaa aaagagaaga tgtgcaataa gattaataaa gtaaattctg    120
aaggcgaatt tgataaagat agagactcta tatctgaaac agtcgactta aacaaccagg    180
aaactgtcaa agtgcaaata cacagcagag cttcagaata tatcactgat gtccattcga    240
atgacctgtc tacaccacag atccttccat caaatgaagg tgttaatcca cgtttatcgg    300
caagccctcc taaatcaggc aatttgtggc caggattggc accaccacac aaaaaagctc    360
agtctgcatc tccaaagaga aaaaaacagc acaagaaata cagaagtgtt atttcagaca    420
tatttgatgg aacaatcatt agttcagtgc agtgtctgac ttgtgacagg gtgtctgtaa    480
ccctcgagac ctttcaagat ctgtccttgc caattcctgg caaggaagac cttgctaagc    540
tgcattcatc aagtcatcca acttctatag tcaaagcagg atcatgtggc gaagcatatg    600
ctccacaagg gtggatagct tttttcatgg aaatatgtga agaggtttgt tgtctcatgt    660
gtccctagct ggttttgggg tccagtagta accttgcaag attgtcttgc tgccttcttt    720
gccagagatg aactaaaagg tgacaatatg tacagttgtg aaaaatgcaa aaagttgaga    780
aatggagtga agttttgtaa agtacaaaac tttcctgaga ttttgtgcat ccaccttaaa    840
agattcagac atgaactaat gttttccacc aaaatcagta cccatgtttc atttccgcta    900
gaaggcttgg atcttcagcc atttcttgct aaggatagtc cagctcaaat tgtgacatat    960
gatcttctgt cagtcatttg ccatcatgga actgcaagta gtgggacact atattagcct   1020
tactgccgaa acaatctaaa taatctctgg tatgaatttg atgatcagag tgtcactgaa   1080
gttttcgagt ctacggtaca aaatgcagaa gcttacgttc ttttctatag gaagagcagc   1140
gaagaggcac aaaaagagag gagaaggata tcaaatttat tgaacataat ggaaccaagc   1200
ctccttcagt tttatatttc tcgacagtgg cttaataaat ttaagacctt tgccgaacct   1260
ggccctattt caaataatga ctttctttgt attcatggag gtgttcctcc aagaaaagct   1320
ggttatattg aagacctggt tttgatgctg cctcagaaca tttgggataa cctatatagc   1380
aggtatggtg gaggaccagc tgtcaaccat ctgtacattt gtcatacttg ccaaattgag   1440
gcggagaaaa ttgaaaaaag aagaaaaact gaattggaaa tttaaattca gcataacaga   1500
gcgttccaaa aagaggactc tccagctact ttttattgca tcagtatgca gtggtttaga   1560
gaatgggaaa gttttgtgaa gggtaaagat ggagatcctc caggtcctat tgacaatact   1620
aagattgcag tcactaaatg tggtaatgtg atgcttaggc aaggagcana ttctggccng   1680
atttctgaag aaacatggaa ttttctgcag tctatttan                          1719
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 228
<211> LENGTH: 629
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  228
gtncggtttg aacnagagac naaagctgtt gccngcttca tagagagcaa gaaggatgat     60
attttgtgct tcctgaccat gcactcttat gggcagttaa ttctcacacc ttacggctac    120
accaaaaata aatcaagtaa ccacccagaa atgattcaag ttggacagaa ggcagcaaat    180
gcattgaaag caaagtatgg aaccaattat agagttggat cgagtgcaga tattttatat    240
gcctcatcag ggtcttcaag agattgggcc cgagacattg ggattccctt ctcatatacg    300
tttgagctga gggacagtgg aacgtatggg tttgttctgc cagaagctca gatccagccc    360
acctgtgagg agaccatgga ggctgtgctg tcagtcctgg atgatgtgta tgcgaaacac    420
tggcactcgg acagtgctgg aagggtgaca tctgccacta tgctgctggg cctgctggtg    480
tctgcatgtc tcttctctaa gtgcattctg gccaggcctg ctcaacccca gtggcatgag    540
tgtggctgga ggaacggggt ntatggttgt aaagaaacca aataattaac taaaaatact    600
tctatttaat aaggaaaaaa aaaaaaaaa                                      629
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 229
<211> LENGTH: 653
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: zinc carboxypeptidases
<400> SEQUENCE:  229
caagttattt ggataaatgg gaacaaagaa aagaaaacag cctcagcctc cagccttccc     60
ttttgggacc tgcctcacaa tgcaccctct cttccaggca cttcttgatt tccaaaagga    120
aaccaccagt gagtgagtcc actatgaagc ttactaccag gttggtttaa tttgcatggg    180
tcccagacga agtctcaagg gcccagaagg gtcacccacg ctgtcgtctc ttccgccccc    240
gcagcttcag ccgcctggct ggcaggctga cgggctgctt cccaaacttc tccatgatct    300
ctcggatcct ggccatgttg gttttgctaa gtgtgaagtc acaccttgtg gcccccatgt    360
catagccaac catacagttc ttggtggatg cagtgaaacc ttcggccttt gctgtgacca    420
catactctcc agggttcagg aggcgccagt aatccccatc gttggctgtt cggatgtcat    480
ggttaatgcc ttctacggag ataatggcgt ttgggattcc gttttccatg tgaatctctc    540
accaagcctt taatgccacg atgaacctgc tgcatgaaca cgatcagaga gtacctgtta    600
ttatctcact cctncggcag ctgcctctca tgtgggtatt tatcacagcc cac           653
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 230
<211> LENGTH: 796
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  230
gtccggggag aggccaggag cggctccgtt tggcttggtg gctgcaggcc caggctgtcg     60
cgctgcgctc ggtgagtgca ggatccagca tccaggatgt ggtggtcctt gatccttctt    120
tcttgcctgc tggcactgac cagtgcccat gacaagcctt ccttccaccc gctgtcggat    180
gacctgatta actatatcaa caaacagaat acaacatggc aggctggacg caacttctac    240
aatgttgaca taagctatct gaagaagctg tgtggcactg tcctgggtgg acccaaactg    300
ccaggaaggg ttgcgttcgg tgaggacata gatctacctg aaacctttga tgcacgggaa    360
caatggtcca actgcccgac cattggacag attagagacc agggctcctg cggctcttgt    420
tgggcatttg gggcagtgga agccatttct gaccgaacct gcattcacac caatggccga    480
gtcaacgtgg aggtgtctgc tgaagacctg cttacttgct gtggtatcca gtgtggggac    540
ggctttaatg gtggctatcc ctctggagca tggagcttct ggacaaaaaa aggcctggtt    600
tcaggtggag tctacaattc tcatgtaggc tgcttaccat acaccatccc tccctgcgag    660
caccatgtca atggctcccg tcccccatgc actggagaag gagatactcc caggtgcaac    720
aagagctgtg aagctggcta ctccccatcc tacaaagagg ataagcactt tgggtacact    780
tcctacagcg tgtcta                                                    796
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 231
<211> LENGTH: 586
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  231
gacaagtgaa agggtttata caagcaaaaa gaatgtacac tttctggcaa gagaatacag     60
aagagatttg aatgtcatga agatattaaa aaaaaaagaa tacagaggag ataagagact    120
tgagtaagaa taggtcatgt tttaataaaa ctaccaaaag aacaaaacag attcttcaac    180
ccaggaggac atgtgagtca caataccctt taatccacag gttggctcct tggtttctgg    240
aactttctgc ctcctgtaaa cgatgtgcgg gtggtaccct ccctcaacca gtggatgctt    300
cttcacgggt tcaatgaaaa agtctccatg tggtagttgg aaaaatccag tcagtccatg    360
gcaggcactg agggctgccg tcccaactct ggtgccctgc tgtagaaccg tgccactgag    420
atggcagagg ggggcagagg aagccatcat cttaacatgg gagaggttcc catatctctt    480
ctccatgatg tagctattgg aaagaaatcc ttcattgacc gtcaagttaa aaaacaggtc    540
cttctcctcg tgagaaattc tgtagtacac ccagtcctct gagccn                   586
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 232
<211> LENGTH: 644
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  232
tggtcgcggc cgaggtacct ttattgttcc atgttatagt gtaatatttc agtagttctt     60
ttcatggtta gttaaatcct aagccaatga caaaaagaaa atggtaacca gatgtgaaac    120
tccgcttcct ctcctctgta tcataacaca acncattcat cctggctctt tggcggttca    180
ctttcttgtc ctcatcagga agtggagtca ttggataggg gtattttatg ctggaggcaa    240
tagacccagt tgatgaagaa ggagacttgg caggagataa agtctcagtt gaattagacc    300
cgaggtctaa atcttttgcc tctgattntc tttttgttgc ctcccaggtt accttgccaa    360
gagttacttc gaggtcgccc attttcacaa gatgtctgaa atatgttttg tgtctggaat    420
cctttcactc caagaatgag agagcccatt tgacctctgt tctcgatagg ttttatancc    480
ccacgcagtt attcctaata tnagggccag cnctaaaatg gtgccagcaa ttatgcctat    540
tatgatattg gtgccagcaa caccattgcc agacagagtg ataccagtct ttgcatcatc    600
attgtgaggg aagtaagtgt tgcaatcaga acctatccag tgtn                     644
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 233
<211> LENGTH: 430
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ADAM family of metalloprotease
<400> SEQUENCE:  233
cgtccggcat tatgccccaa caacaggcat aangcaagat ggctcaaaat gtcatacaat     60
ttacgagtgc cttaaagttc attgtatgga ccctaataat cagtgcttac aattatatgg    120
atatggtgca aaatcagcct cacaagagtg ttacaattca atgaacagca aaggggacca    180
atttggaaac tgtggcattt ctaccagtcc tgggtcacaa tatgttcggt gttcagatgg    240
taatatattt tgtgggaaac ttatatgttc aggtattaca ggcttaccaa aaatcaatct    300
ccaacataca atgattcagg tccctcaggg agatggctca tgttggagca tggatgccta    360
tatgagtact gacattcctg atgaaggaga tgtgcacaat ggcacttact gtgcaccaaa    420
caaagtctgc                                                           430
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 234
<211> LENGTH: 491
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  234
tcggcggccg cccgggcagg tacatttctc tttgtcatga attgcatact ttgttccaag     60
tcatgtggtc tggaaagtgg gcgttggtct caccatttgc tatgctacac tcagtgtgga    120
gactcattcc tgcctttcgt ggttacgccc aacaagacgc tcaggaattt ctttgtgaac    180
ttttagataa aatacaacgt gaattagaga caactggtac ctgatcctaa tccagttccg    240
gattgacctc cgcttgtaga tgaaccagat cctggttgtt gtgatttatc tgtattagtt    300
tgtccacatg aaatagctat tagaggtatt aaagctagtg ccacaagcga accaaaacta    360
actaataatt tctttgaaaa tatcgatttt ttcacttttc ctcaattctt tattttctta    420
aataaattaa taaataaaag caaaaataaa agaagtgtgc attatttgtg tgtgacctcg    480
gccgcgacca c                                                         491
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 235
<211> LENGTH: 237
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  235
agnggccgcn cgngcaggna cagaccccat aacacagatt aaccaagtta ctcatgatca     60
agcagtgntg ctacaaagtg ccnttnagag cattcctaat ccctcatccg nntgcatgct    120
tagaaatgtg tnanttcgtc ttgctcanca gatatctgat gaggctnnaa gatatatgcc    180
tgatatttgt gtaattagag ctntacaaaa aatnatctgg gcatcaggat gtgggtc       237
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 236
<211> LENGTH: 384
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  236
cgtccggtga cccgcggctg ggcgcctcgg ccatgactgc ggagctgcag caggacgacg     60
cggccggcgc ggcagacggc cacggctcga agttatagac cttactcatg ataacaaaga    120
tgatcttcag gctgccattg ctttgagtct actggagtct cccaaaattc aagctgatgg    180
aagagatctt aacaggatgc atgaagcaac ctctgcagaa actaaacgct caaagagaaa    240
acgctgtgaa gtctggggag aaaaccccaa tcccaatgac tggaggagag ttgatggttg    300
gccagttggg ctgaaaaatg ttggcaatac atgttggttt agtgctgtat tcagtctctc    360
tttcaattgc ctgaatttcg aaga                                           384
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 237
<211> LENGTH: 931
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  237
cgcgtccgcc cacgcgtccg gtttgctttg cgggagctga caggctcgct cttggcactc     60
attgagatgg tagtgtactg ctgtttctgt aatgagcatt tttccttcac aatgctgcat    120
ttcattaaga accaactaga aacggctcca cctcatgagt taaagaatac gttccaacta    180
cttcatgaaa tattggttat tgaagatcct atacaagcag agcgagtcaa atttgtgttt    240
gagacagaaa atggattact agctttgatg caccacagta atcatgtgga cagtagtcgc    300
tgctaccagt gtgtcaaatt tcttgtcact cttgctcaaa agtaagtatt gaattaaaat    360
gcagggagga aatggtgttt taattacaag tcacatatga gcagaagggg aacatgtgcc    420
cggttttgat acctggagaa tctgactcag tcagggcctg cttgcttgga aggtacagaa    480
acctatttgc atgatctcaa aaaaatatga ggggaagtat taaaagagtg acagatcttt    540
atagaatccc agaaaagctc acccatcagg ccttatgtca gaaaggcagg aatcagggca    600
gatatggagg ctttaagagc aagagttcat gagctttcac tcaaggtttc tcattaatgt    660
aacccagcta ccagctcttc aggctctagg tccctaacct cagaatagcc tttcaaatca    720
tgtcacctgt agctcctgag cacttgtgaa cccaggcacc ngtgtcaaga accttgcctg    780
tattatctta tttcatcttt gtaacaactt catgaggtta gtacagttgt gagtcatata    840
tcatgggtag tntaagtgac atgcctagaa tcatagaatg aaaacttgaa cacaggctga    900
ttgactgcaa aatgaangtt cttttttttt n                                   931
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 238
<211> LENGTH: 809
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  238
tggattacta gctttgatgc accacagtaa tcatgtggac agtagtcgct gctaccagtg     60
tgtcaaattt cttgtcactc ttgctcaaaa gtgtcctgca gctaaggagt acttcaagga    120
gaattcccac cactggagct gggctgtgca gtggctacag aagaagatgt cagaacatta    180
ctggacacca cagagtaatg tctctaatga aacatcaact ggaaaaacct ttcagcgaac    240
catttcagct caggacacgt tagcgtatgc cacagctttg ttgaatgaaa aagagcaatc    300
aggaagcagt aatgggtcgg agagtagtcc tgccaatgag aacggagaca ggcatctaca    360
gcagggttca gaatctccca tgatgattgg tgagttgaga agtgaccttg atgatgttga    420
tccctagagg aacatgccca gcctgagagg agtcaagaca caatactgga tgctcagcac    480
cttcttggaa tcagaatctc gaaccctttg gaagagcctg gagattggac tgggaaagct    540
tgctgtgact tgggccggat cgtgtatttc tcaaggaaag catttttaag ccctagaagg    600
tttgggagct gtttggcagt gggagaactc cggcatgtgg atcagctgtc ccgggagcgt    660
ggtctatatg tggattcaca tttctgtgga gatttcggaa tagagccagt ggcagacttt    720
tttgttcacg aacataccaa gagtgacata agctggtgct ttctctccga tgctacaaaa    780
gaaattcctt tggnntttat attttaagn                                      809
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 239
<211> LENGTH: 859
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  239
aaaacgacag gcccttgcct tcccggtccc ggaaagatgg gaactcctgt gcttcgtgcc     60
catggtatac gattttgcag aggctgtaaa attgattgtg gggaagacag agctttcatt    120
ggaaatgcct atatcgctgt ggattgggat cccacagccc ttcaccttcg ctatcaaaca    180
tcccaggaaa gggttgtaga tgagcatgag agtgtggagc agagtcggcg agcgcaagcc    240
gagcccatca acctggacag ctgtctccgt gctttcacca gtgaggaaga gctaggggaa    300
aatgagatgt actactgttc caagtgtaag acccactgct tagcaacaaa gaagctggat    360
ctctggaggc ttccacccat cctgattatt caccttaagc gatttcaatt tgtaaatggt    420
cggtggataa aatcacagaa aattgtcaaa tttcctcggg aaagttttga tccaagtgct    480
tttttggtac caagagaccc ggctctctgc cagcataaac cactcacacc ccagggggat    540
gagctctctg agcccaggat tctggcaagg gaggtgaaga aagtggatgt gcagagtttg    600
gctggggaat aggacatgct cctgagcaaa agcccatcct cactcagcgc taacatcatc    660
agcagcccaa aaggttctcc ttcttcatca agaaaaagtg gaaccagctg tccctccagc    720
aaaaacagca gccctaatag cagcccacgg actttggggg gaggagcaaa ggggggctct    780
ggctgcccca nattggcngc aaaaataaac tgtcaagtng taagaagaac ttggatgcca    840
gcaaagagaa tggggctgn                                                 859
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 240
<211> LENGTH: 594
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  240
nccccgcgtc cgcactgcac tgcagcctgg gcaacagagt gagaccctgt ctgaaaataa     60
ataaataaat aaatattata aataaataag tgtgaacatt gattaccacc attttattga    120
tgggaaaacc aaaaccagaa ggttaaattt tctcagtttc ctgttttatt aatacctacc    180
tctacctacg attatatatg ccagttttta ctagtaacaa gcttatatcc atgttctagg    240
tggtctggcc gtaatcatcg agagaagatt ggggtccatg tcgtctttga ccaggtatta    300
accatggaac cttactgctg cagggacatg ctctcctctc ttgacaaaga gacctttgcc    360
tatgatctct ccgcagtggt catgcatcac gggaaagggt ttggctcagg acactacaca    420
gcctattgct acaacacaga ggggaggtgc gtgcgcttta ctctgtgggg tgggggacac    480
ggaaaggggt tgatttgcca cattttattg gtttcctttt atttccatcc catggattac    540
ctagagggaa attacataca tcaaaaatnc agtggaaaga attgtgaaaa ttgg          594
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 241
<211> LENGTH: 199
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  241
ggggggaagc agcgngcgca gccggaggat cgcggagtcc caatgaaacg ggcanccatg     60
gccctccaca gcccgnagta tatntnnggn gatgnnagcc ctgatgaatt naatnaattn    120
tttgtgactc ctngatcttc aggtgagctt nctccataca gnggnacant tctgtgnggc    180
acacangctg tggataaac                                                 199
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 242
<211> LENGTH: 389
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolses family
2
<400> SEQUENCE:  242
gaaagtacct tttcttctcc tgaagattct ttacccaagt ctaaaccact gacatcttct     60
cggtcttcca tggaaatgcc ttcacagcca gctccacgaa cagtcacaga tgaggagata    120
aattttgtta agacctgtct tcagagatgg aggagtgaga ttgaacaaga tatacaagat    180
ttaaagactt gcattgcaag tactactcag actattgaac anatgtactg ngatcctntc    240
cttcgtcagg tgccttatcg cttgcatgca gttcttgttc atgaaggaca agcaaatgct    300
ggacactatt gggcctatat ctataatcaa ccccgacaga gctggctcaa gtacaatgac    360
atctctgtta ctgaatcttc ctgggaaga                                      389
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 243
<211> LENGTH: 1094
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  243
ccncgcntcc ggacccgtgg gaaacaggtc ttgaagctga cccatttgcc ccagaccctg     60
acaatccacc tcatgcgatt ctccatcagg aattcacaga cgagaaagat ctgccactcc    120
ctgtacttcc cccagagctt ggatttcagc cagatccttc caatgaagcg agagtcttgt    180
gatgctgagg agcagtctgg agggcagtat gagctttttg ctgtgattgc gcacgtggga    240
atggcagact ccggtcatta ctgtgtctac atccggaatg ctgtggatgg aaaatggttc    300
tgcttcaatg actccaatat ttgcttggtg tcctgggaag acatccagtg tacctacgga    360
aatcctaact accactggca ggaaactgca tatcttctgg tttacatgaa gatggagtgc    420
taatggaaat gcccaaaacc ttcagagatt gacacgctgt cattttccat ttccgttcct    480
ggatctacgg agtcttctaa gagattttgc aatgaggaga agcattgttt tcaaactata    540
taactgagcc ttatttataa ttagggatat tatcaaaata tgtaaccatg aggcccctca    600
ggtcctgatc agtcagaatg gatgctttca ccagcagacc cggccatgtg gctgctcggt    660
cctgggtgct cgctgctgtg caagacatta gccctttagt tatgagcctg tgggaacttc    720
aggggttccc agtggggaga gcagtggcag tgggaggcat ctgggggcca aaggtcagtg    780
gcagggggta tttcagtatt atacaactgc tgtgaccaga cttgtatact ggctgaatat    840
cagtgctgtt tgtaattttt cactttgaga accaacatta attccatatg aatcaaagtg    900
ttttgtaact gctattcatt tattcagcaa atatttattg atcatctctt ctccataaga    960
atagtgtgat aaacacagtc atgaataaag ttattttcca caaaaaaaaa aaaaannnnn   1020
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nacacctncc cntnaacctn nacataaatg   1080
aatgcaattg gttn                                                     1094
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 244
<211> LENGTH: 466
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  244
cgtctgtctg gccattggct ttgccgtgct gcttcgggcg ctgtggaagg gcacccacca     60
tgccttccag ccttccaagt tgaaggccat tgtggcgagt aaggccagcc agttcacagg    120
ctatgcacag catgatgccc aggagttcat ggctttcctg ctggatgggc tgcacgagga    180
cctgaatcgc attcagaaca agccctacac agagaccgtg gattcagatg ggcggcccga    240
tgaggtggta gctgaggaag catggcagcg gcacaagatg aggaatgact ctttcatcgt    300
ggacctattt caggggcagt acaagtcgaa gctggtgtgc cctgtgtgtg ccaaggtctc    360
catcactttt gacccgtttc tttatctgcc gggtgccctt gccacaaaag caaaaggttc    420
tccctgtctt ttattttgcc cgagagcccc acagcaagcc catcaa                   466
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 245
<211> LENGTH: 518
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  245
cgcaagatgc cttccaatga aagctgaaga ggagacggat gaagagaagc caaagaaccc     60
catggtagag ttgttctatg gcagattcct ggctgtggga gtacttgaag gtaaaaaatt    120
tgaaaacact gaaatgtttg gtcagtaccc acttcaggtc aatgggttca aagatctgca    180
tgagtgccta gaagctgcaa tgattgaagg agaaattgag tctttacatt cagagaattc    240
aggaaaatca ggccaagagc attggtttac tgaattacca cctgtgttaa catttgaatt    300
gtcaagattt gaatttaatc aggcattggg aagaccagaa aaaattcaca acaaattaga    360
atttccccaa gttttatatt tggacagata catgcacaga aacagagaaa taacaagaat    420
taagagggaa gagatcaaga gactgaaaga ttacctcacg gtattacaac aaaggctaga    480
aagatattta agctatggtt ccggtcccaa acgattcc                            518
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 246
<211> LENGTH: 1102
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 2
<400> SEQUENCE:  246
agatccagca tcatcaccca gtatacaaga tggtggtcta atgcaagcct ctgtacccgg     60
tccttcagaa gaaccagtag tttataatcc aacaacagct gccttcatct gtgactcact    120
tgtgaatgaa aaaaccatag gcagtcctcc taatgagttt tactgttctg aaaacacttc    180
tgtccctaac gaatctaaca agattcttgt taataaagat gtacctcaga aaccaggagg    240
tgaaaccaca ccttcagtaa ctgacttact aaattatttt ttggctccag agattcttac    300
tggtgataac caatattatt gtgaaaactg tgcctctctg caaaatgctg agaaaactat    360
gcaaatcacg gaggaacctg aataccttat tcttactctc ctgagatttt catatgatca    420
gaagtatcat gtgagaagga aaattttaga caatgtatca ctgccactgg ttttggagtt    480
gccagttcca aagaattact tctttctctt cattgtcaga aagttggtct gtagatgttg    540
acttcactga tcttagtgag aaccttgcta aaaaattaaa gccttcaggg actgatgaag    600
cttcctgcac aaaattggtg ccctatctat taagttccgt tgtggttcac tctggtatat    660
cctctgaaag tgggcattac tattcttatg ccagaaatat cacaagtaca gactcttcat    720
atcagatgta ccaccagtct gaggctctgg cattagcatc ctcccagagt catttactag    780
ggagagatag tcccagtgca gtttttgaac aggatttgga aaataaggaa atgtcaaaag    840
aatggttttt atttaatgac agtagagtga catttacttc atttcagtca gtccagaaaa    900
ttacgagcag gtttccaaag gacacagctt atgtgctttt gtataaaaaa cagcatagta    960
ctaatggttt aagtggtaat aacccaacca gtggactctg gataaatgga gacccacctc   1020
tacagaaaga acttatggat gctataacaa aagacaataa actatattta caggaacaag   1080
agttgaattg ctctgcccca gc                                            1102
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 247
<211> LENGTH: 544
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: hemoglobinase
<400> SEQUENCE:  247
ccgcttagaa ctccaaattg gcctcccagg caaggatcta aaacttcacc aaatcatttc     60
tcccaggcag acgcgtgcca tgcctaccag atcattcacc gcaatgggat tcctgacgaa    120
cagatcgttg tgatgatgta cgatgacatt gcttactctg aagagtaagt ggggaacact    180
tggaacttgg tggggaagga cttcagggta tttaaaaaaa ggtcacatag actcacagga    240
atcctagtgg cctaatgtta aaatatataa gagactccca gacagaagat cacagggata    300
cctcatgttg agcttttttt tttttattat tatttatttg agacagtctt gctccagcct    360
gagtgacaga gtgagactct gtctcaaaca cacacacaca cacacacaca cccncaccct    420
gaccaacagt gtgaatcccc gtctctacta aaaatacaaa aattaaccag gcgtggtggc    480
gtgtgcctat aatcccagct actcgggagg ctgaggcagg agaactgctt taacctggga    540
ggcg                                                                 544
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 248
<211> LENGTH: 554
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: prolyl oligopeptidases
<400> SEQUENCE:  248
gtccggtcaa aatggtcact ttatattgtt atgtagttaa tatattttag agcaaatatt     60
ccaaattttg taatttgctc cttttaaaaa acaagcataa gataggcatc taacctagaa    120
tttcctttat tttagatgaa ctcacaaatt cgtcagaaac cagattgtct ttggaagacc    180
tctttaggaa agactttgtg cttcacgatc cagaggctcg gtggatcaat gatacagatg    240
tggtgtataa aagcgagaat ggacatgtca ttaaactgaa tatagaaaca aatgctacca    300
cattattatt ggaaaacaca acttttgtaa ccttcaaagc atcaagacat tcagtttcac    360
cagatttaaa atatgtcctt ctggcatatg atgtcaaaca ggtaaaggag tgatcttctt    420
tgagaatact tttctttgtg atgcattggg gtgacaatgc ataattttac tcagctataa    480
ctcacctaag caaaatctgg catgtctagt aactaccgga ggacagtaat gactactttg    540
cacaaaagat gttt                                                      554
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 249
<211> LENGTH: 547
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: prolyl oligopeptidases
<400> SEQUENCE:  249
acaaatgcta ccacattatt attggaaaac acaacttttg taaccttcaa agcatcaaga     60
cattcagttt caccagattt aaaatatgtc cttctggcat atgatgtcaa acagattttt    120
cattattcgt atactacttc atatgtgatt tacaacatac acactaggga agtttgggag    180
ttaaatcctc cagaagtaga ggactccgtc ttgcagtacg cggcctgggg tgtccaaggg    240
cagcagctga tttatatttt tgaaaataat atctactatc aacctgatat aaagagcagt    300
tcattgcgac tgacatcttc tggaaaagaa gaaataattt ttaatgggat tgctgactgg    360
ttatatgaag aggaactcct gcattctcac atcgcccact ggtggtcacc agatggagaa    420
agacttgcct tcctgatgat aaatgactct ttggtaccca ccatggttat ccctcggttt    480
actggagcgt tgtatcccaa aggaaagcan gtatccgtat cctaaggcag gtcaagtgaa    540
cccaaca                                                              547
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 250
<211> LENGTH: 821
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  250
tggtcgcggc cgaggtacgt ggccagtcaa tggcaggttc accgcacctc aggcagaact     60
ctatgaagcc gttctagaga tccaaagaga ttgtttggcc ctctgcttcc ctgggacaag    120
cttggagaac atctacagca tgatgctgac cctgatagga cagaagctta aagacttggg    180
gatcatgaag aacattaagg aaaataatgc cttcaaggct gctcgaaaat actgtcctca    240
tcatgttggc cactacctcg ggatggatgt ccatgacact ccagacatgc cccgttccct    300
ccctctgcag cctgggatgg taatcacaat tgagcccggc atttatattc cagaggatga    360
caaagatgcc ccagagaaag tttcggggtc ttggtgtacg aattgaggat gatgtagtgg    420
tgactcagga ctcacctctc atcctttctg cagactgtcc caaagagatg aatgacattg    480
aacagatatg cagccaggct tcttgacctt cactgcggcc cacatgcacc tcaggttcaa    540
aatgggtgtc ttctggcagc cctgcacgtg tgctttctga gtgtctctgt gtgtgcatta    600
atatatgcat tccatttggg agcatagcag ctgtgtgaat gtatgtaatt gtgtgtgggg    660
ggttttttgt tttaagtagt tagaagtctg ggaaaatgaa tttttgaata gtatgttact    720
gcagctttgg taacattaat tctatagaat taatgatcag agcaagttta atttttaanc    780
ataaaggtct tggttacaca tgtccatgca ttccagttaa n                        821
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 251
<211> LENGTH: 449
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  251
agccaagagc aagaacaagg ttcggggtgt tcagcagctg atacagcgcc tccggctgat     60
caagtctcct gcagaaattg aacgaatgca gattgctggg aagctgacat cacaggcttt    120
catagaaacc atgttcacca gtaaagcccc tgtggaagaa gcctttcttt atgctaagtt    180
tgaatttgaa tgccgggctc gtggcgcaga cattttagcc tatccacctg tggtggctgg    240
tggtaatcgg tcaaacactt tgcactatgt gaaaaataat caactcatca aggatgggga    300
aatggtgctt ctggatggag gttgtgagtc ttcctgctat gtgagtgaca tcacacgtac    360
ctcggccgcg accaccagct ttcacaaatt agctgacatt ttaaaagtat tttattgctt    420
attaaaatgg tttttacaga cattatctn                                      449
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 252
<211> LENGTH: 496
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  252
gtggtcgcgg cgaggtacga cctattccat gaccagaaaa ttctttaggc gtgtataaat     60
tattttgttt gattacttta aaaattgcat tagcaatgtc taaagttgta gcatcttttt    120
taatagcgtt gaatcctgct caaaatgcac tttcagcaac atcaatgatt ttttgatctt    180
gataagatac tttacctact gcttttgtaa aggcactatc agcgtgaaat ccttcaaaag    240
caagacccca aatcaatgga gacaacatca gattcttgaa ttacataatc cgttggtata    300
ccatgaatta atacattatt aacactagcg caaattgttg ctggaaaacc ttgatagttt    360
aaaaatggaa gggttagcat ttcttttttc gatctcttta aaagcgatgg catctaattc    420
ttttaaagaa acacctggtc ttacaaggtc ataaataatt tgttttacct ctgccaggag    480
ctgaccagct ttaatt                                                    496
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 253
<211> LENGTH: 363
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  253
tcgccagcga ngctnaccgt gcctttnata tgcaccgcgc cggccactgg ctgggcatgg     60
atgtgcacga tgtgggcgaa tacaaagtgg gcggtgaatg gcgagtgctg gaagtgggca    120
tggccttgac cgtggagccg gggatttata tttcgccgga caaccagaac gtggcaaaga    180
aatggcgtgg cattggcgta cgcatcgagg atgacgtggt agtgaccaag caaggctgtg    240
aaattctgac cggtggtgtg cctaaaactg tcgctgagnt cgaagcgctg atggcggctg    300
cccgatgagc cgggtcaacc tgggcgatta tcggtggtgg cctgggtngg cgccactggg    360
cgt                                                                  363
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 254
<211> LENGTH: 438
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: c15 thiol protease family
<400> SEQUENCE:  254
ccncgcgtcc gccggccgct gggccgctgc ctgagccagg gaggcgcagc gcgagctccc     60
acttcgtctt catggattcc cagcccagct gcgtggtggt gactggtttt gggcccttcc    120
ggcagcactt ggtgaattcc agctgggaag cagtgaagga gctctccaag ctgggcctgg    180
ggaatgaaac agtggtgcag ctgcggactc tggagctgcc tgtagattac agggaggcta    240
agcggagggt caccggaatc tgggaagatc atcagccgca actcgtcgtg catgtgggca    300
tggacaccgc cgccaaggcg atcattctgg aacagtctgg caagaaccaa ggctaccggg    360
acgccgacat ccgcagcttc tggcccgagg gcggcgtgtg cctacctggc agcccagacg    420
tgctggagtc aggggtct                                                  438
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 255
<211> LENGTH: 642
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: neprilysin family of protease
<400> SEQUENCE:  255
tttttttttt tttcaacaga gacaggttta ttttgggaat aaacctgaga ggggcttctg     60
gccgatttcg gtcagggaca ttctcttaca gactaagggc atttaagggt ttaggaaggg    120
ggagcctacc gcagcctgcg aatgtttttt gtgtgaagga gagttttatt gcagagttgg    180
aatatctctg gctggagggg aggttattct caggattggc atgtttctgg tcagatgggg    240
gtttatctca tggttgaaat gtttctgctc atactgacat gagccattag gctgatgttt    300
tgggctggtt tttaatcacg gagaacttaa aatggccatg tttgtccaag atggcaatgc    360
tcctgctgtc acacccaccc acccacaggg tactcggggt cgctgcagaa cctggccgcc    420
ttcgcagaca cgttccactg tgcccggggc acccccatgc accccaagga gcgatgccgc    480
gtgtggtagc caaggccctg ccgcgctgtg cggcccacgc ccacccgctg ctcggaggca    540
tctgtgcgaa ggtgcagcta gcggcgacca gtgtagtccg cccggccaac atgcaacctg    600
ctgccagctc tggctggcta gggtcagcac ctgctgaacc ag                       642
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 256
<211> LENGTH: 400
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: cathepsin
<400> SEQUENCE:  256
caggggatca ttgcaaggtg gctcctctag tgtggcttcc agggagaaca gagagccctg     60
gccggcccgg cggacgcgtc cgcgcaccgc tcctagcacg gcccttgtcc ccgcagcacg    120
gccgtaattg tacatgtcca gcgcgaagcg ggcgggggcc agcagctcct gggacgacaa    180
gttccaggcc tgctcgtcat ctgcccaggg cttggcgggg acggggctca gagccacagt    240
cgagagcagt gtcagcagcc acagaagctg cagtaggggc gccatagcga ggtcgaagct    300
gctcgcccgg attcactgac ccacaaacac acggatcaag agacccgagg cggagcctgc    360
tgtcagaggc cacagagagc ggacgcggct cgatccctaa                          400
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 257
<211> LENGTH: 546
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  257
aactgaaaca gttggctcga caggcactag acagagcaga agcgctgagt gagcctttga     60
ccaagccagt tggcaaaatc agttcaacaa gtgttaagcc aaagccacct ccagtgagag    120
cacattttcc actgggcgct aatcccttcc ttgaaagacc tcagtcattt ataagtcctc    180
agtcatgtga tgcacaagga cagagataca cagcagaaga aatagaagta ctcaggacaa    240
catcaaaaat aaatggtata gaatatgttc ctttcatgaa tgttgacctg agagaacgtt    300
ttgcctatcc aatgcctttc tgtgatagat ggggcaagct accattatca cctaaacaaa    360
aaactacatt ttccaagtgg gtaccgacca gaagacctca ccaacaatcc tacaatgata    420
tatactgtgt ccagttttag cataaagcag acaatagtat cggattgctc ctttgtggca    480
tcactggcca tcagtgcagc ttatgaaaga cgttttaata agaagttaat tcccggcata    540
atttac                                                               546
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 258
<211> LENGTH: 555
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  258
ccgccagtgt gctttaaagg ctggcctcac ccagctctgc tgctctgttg gtcatgggag     60
caaggtggac ttgccctgga ccttccctac ttgtgctcct ctgttatggg cagctcttgc    120
cttggctcag gatcaagggt gaacacagtt taggtgtggc tgggacccca agaagcatgg    180
gaccagacaa agggactggg tgcggacagg accttctcag cacatgatgc ccatatcctt    240
ccctgcagat gacttctaca atgagaccga gaccaagatc ttcctgcagg ttttatgacc    300
aaacaggtga agttgtgttg aacaagttca tggaggccac ttggaactat gtcaccaata    360
tcaccaggaa aaatcaggag gagatgatgt gataccacct ccaccccagc ctctcctctc    420
tttgctcttt ttagggattt gggaccatgg ggcaccacac ctcctgcccc catcccaagc    480
aagaggaaca agggaagccc cagtgtacat gtcaaagagg gctgcaantc tgggcctcct    540
ggaagcccta atctt                                                     555
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 259
<211> LENGTH: 831
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  259
taacggccgc cagtgtgctc taaaggcaaa cacacaatta caatatcaca tgtacccaga     60
tctgccacag ctgaacccaa ttataattgg gcactatgca tgcaggctgt cccctcctct    120
gccccccaac tctctggctc agcctccctc ctcctgcccc ccagcctcac cagttcactg    180
gtgtctagtc ccaacttcac cattcagctc ttacccttgg aggctttcct ggctttactg    240
tgtgaaaatc cagatggcca ggctgattga gcacagcatc aggacaaggc agaggcccag    300
cagcatccac tgtcctttag cagcctggca gggttccatg gctatgccca ggaagcaggc    360
attgggcagt gggctgaata tctcagtgtc ttgagtcagt gactgttttt ccagggactg    420
cagcctgcag gccacgcccc agcaccacca gagacatgac aaagcccagg gccaacagca    480
cccagtaccc aaatttagcc tggttggggt ccagcttcag actcaggaat gtcactttgt    540
ctgtgtcttt ttctgtggaa gacataggag tctcataggg tgggtagaac tggagaggga    600
cccctggggt ctcctgtggc tgtcagagga gatctgattg gactacatgc ccctgcatgc    660
aagggaccag aggcaagatg ctgatccttt gctcagatgt cagcctggca acctagctgg    720
acagtgtgca aggaagcaac tgagccaggg ntgtggtggg agcggtggtc ttggctgaag    780
ctgcatcagg nctggtacag acagggtccc acagcagcag tgctgttgat t             831
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 260
<211> LENGTH: 152
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: angiotensin-converting enzyme
<400> SEQUENCE:  260
ccagcagaaa agtggaactt ggcacctgga tcaaagtctt cctctgagtg aggaatagcg     60
gggcacaagc ctggtatttc aacctggcag ggaaaaggca gagggcttgg tggtggtgtc    120
tggcaggttc tcagagcctc tttcttttcc tt                                  152
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 261
<211> LENGTH: 340
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  261
aacatggcgg cgcccagtgg cgtccacctg ctcgtccgca gaggttctca tagaattttc     60
tcttcaccac tcaatcatat ctacttacac aagcagtcaa gcagtcaaca aagaagaaat    120
ttcttttttc ggagacaaag agatatttca cacagtatag ttttgccggc tgcagtttct    180
tcagctcatc cggttcctaa gcacataaag aagccagact atgtgacgac aggcattgta    240
ccagactggg gagacagcat agaagttaag aatgaagatc agattcaagg gcttcatcag    300
gcttgtcagc tggcccgcca cgtcctcctc ttggctggga                          340
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 262
<211> LENGTH: 245
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: methionine aminopeptidases
<400> SEQUENCE:  262
gtccggcggc ggccaccgga ccctgcgttn nggctgggga atgaaaccct gaaggtgccg     60
ctggcgctct ttgccttgaa ccggnagcag cctgtgtgag cggctgcgga agaaccctgc    120
tgtgcangcc ggctccatcg tggtcctgca gggcggggag gagactcagc gctactgcac    180
cgacaccggg gtcctattcc gncaggagtc cttctttcac tgggcgttcg gngtcactga    240
gccag                                                                245
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 263
<211> LENGTH: 527
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: matrix metalloproteases
<400> SEQUENCE:  263
cgcgtccgcc cacgcgtncg ccccctcaaa cttctgtgca caaagtgctc ccttcccaga     60
ggaggggccc catcggtgtg taaggnggcc tattcctctg tgngtnctct ggatcttttc    120
agccctgtgg tccaatngtc catcacagcc atgctgactg agtgactgga gacagggatg    180
atggagagtt caggaagggc tgggcagagg aggctggggc cacctctgga gggtgtcctg    240
ctgttcctgn tggccccagc tgcactcctn ancccccaac tccattatga ggcccttcta    300
ccagggtccg gtgggcgacc ctgacangtn ccgcgctgtc tcaggatgac cgcgatggcc    360
tgcagcaact ctatgggaag gcgccccaaa ccccatntng acaagcccac aaggaaaccc    420
ctggctcctn cgccccagtc cccggccttc caccacacac agcccatcct ttncccatcc    480
tgatcgatnt gagggcaatt ttngacgcct cgccaacatt cgagggg                  527
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 264
<211> LENGTH: 511
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: calpain
<400> SEQUENCE:  264
ccgcccacgc gtccgcttgc ccaggcgctt aaagaagcaa aatctcttgt gcaggagcag     60
cagagactcc tcaggaagac tcactggact gtacccacca cctgccatgt ctctgtggcc    120
acctttccga tgcagatgga agctggcgcc aaggtactct aggagggcgt ctccacagca    180
accccaacag gactttgagg ccctgctggc agagtgcctg aggaatggct gcctctttga    240
agacaccagc ttcccggcca ccctgagctc catcggcagt ggctccctgc tgcagaagct    300
gccaccccgc ctgcagtgga agaggccccc ggagctgcac agcaatcccc agttttattt    360
tgccaaggcc aaaaggctgg atctgtgcca ggggatagta ggagactgct ggttcttggc    420
tgctttgcaa gctctggcct tgcaccagga catcctgagc cgggttgttc ccctgaatca    480
gagtttcact gagaagtatg ctggcatctt c                                   511
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 265
<211> LENGTH: 663
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: aspartyl proteases
<400> SEQUENCE:  265
cggtctccac cactgctgct gctacccttg ctgctgctgc tgcctctgct gaatgtggag     60
cctgctgggg ccacactgat ccggatccct cttcgtcaag tccaccctgg acgcaggacc    120
ctgaacctac tgaggggatg gggaaaacca gcagagctcc ccaagttggg ggccccatcc    180
cctggggaca agcctgcctc ggtacctctc tccaaattcc tggatgccca gtattttggg    240
gaaattgggc tgggaacgcc tccacaaaac ttcactgttg cctttgacac tggctcctcc    300
aatctctggg tcccgtccag gagatgccac ttcttcaagt gtgccctgct ggttccacca    360
ccgcttcaat cccaatgcct ccagctcctt caagcccagt gggaccaagt ttgccattca    420
gtatgggaac tgggccgggt agatggaatc ctgagtgagg acaagctgac tattggtgga    480
atcaaagggt gcatcccgtg attttcgggg aagctctgtg ggaatccagc ctgggcttca    540
atgnttcccg cccgatggga tattgggcct cgggtttncc attctgnctg tggaaggagt    600
ttcggccccg cttggatgna ctggttggac aaggggctnt ttggtaacct gcttctcctt    660
tta                                                                  663
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 266
<211> LENGTH: 186
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: Lon family of ATP-dependent proteases
<400> SEQUENCE:  266
ccccgcgtcc gcagacatcc atctgcactt cccagctgga gctgtcacaa aagatggacc     60
atctgctgga gttaccatag taacctgtct cgcctcactt tttagtgggc ggctggtacc    120
gttcagatgt agccatgact ggagaaatta cactgagagg tcttgttctt ccagtgggtg    180
gaatta                                                               186
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 267
<211> LENGTH: 543
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 1
<400> SEQUENCE:  267
aggcctccga cctcaaatcc ggaccgattg atttaggtgc atgcaatcaa gatgattgga     60
tcagtgcagt aaggcctgtc atagaaaaaa ggatacaaaa gtacagtgaa ggtgaaattc    120
gatttaattt aatggccatt gtgtctgaca gaaaaatgat atatgagcag aagatagcag    180
agttacaaag acaacttgca gaggaggaac ccatggatac agatcaaggt aatagtatgt    240
taagtgctat tcagtcagaa gttgccaaaa atcagatgct tattgaagaa gaagtacaga    300
aattaaaaag atacaagatt gagaatatca gaaggaagca taattatctg cctttcatta    360
tggaattgtt aaagacttta gcagaacacc agcagttaat accactagta gaaaaggcaa    420
aagaaaaaca gaacgcaaag aaagctcagg aaaccaaatg aagatgtttt cagatatgta    480
cacatttctg cttctgcaca tattttcatg ggaaccatta tgtataaagg ncttngggga    540
can                                                                  543
<200> SEQUENCE CHARACTERISTICS:
<210> SEQ ID NO 268
<211> LENGTH: 781
<212> TYPE: DNA
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<223> OTHER INFORMATION: ubiquitin carboxyl-terminal hydrolases
family 1
<400> SEQUENCE:  268
gtggttgacg agctcggcgg cgggtttgct gagatctgtg gccggcggca gctggtgcgg     60
ggggcacgct gagagcgaga ggtggatcgg ggcggtgtgt ggccagggcc atgacgggca    120
atgccgggga gtggtgcctc atggaaagcg accccggggt cttcaccgag ctcattaaag    180
gattcggttg ccgaggagcc caagtagaag aaatatggag tttagagcct gagaattttg    240
aaaaattaaa gccagttcat gggttaattt ttcttttcaa gtggcagcca ggagaagaac    300
cagcaggctc tgtggttcag gactcccgac ttgacacgat attttttgct aagcaggtaa    360
ttaataatgc ttgtgctact caagccatag tgagtgtgtt actgaactgt acccaccagg    420
atgtccattt aggcgagaca ttatcagagt ttaaagaatt ttcacaaagt tttgatgcag    480
ctatgaaagg cttggcactg agcaattcag atgtgattcg accaagtaca caacagtttc    540
gccagacagc aaatgtttga atttgatacg aagacatcag caaaagaaga agatgctttt    600
cactttgtca gttatgttcc tgttaatggg agactgtatg aattagatgg attaagagaa    660
ggacccgatt gatttaggtg catgcaatca agatgattgg atcagtgcgg taaggcctgt    720
catagaaaaa aggatacaaa agtacctcgg ccgcgaccac gctaaaaatt taatggccat    780
n                                                                    781

Claims

1. A method for producing an isolated polypeptide comprising an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:257 said method comprising introducing a nucleotide sequence encoding said amino acid sequence into a host cell and culturing the host cell under conditions in which the polypeptide is expressed from the nucleotide sequence.

2. A method for detecting the presence in a sample of a polypeptide comprising the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:257 said method comprising contacting said sample with an antibody that specifically allows detection or the presence of the polypeptide in the sample and then detecting the presence of the polypeptide.

3. A kit comprising reagents used for a method for detecting the presence in a sample of a polypeptide comprising the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:257 wherein the reagents comprise an agent that specifically binds to said polypeptide.

4. A method for identifying an agent that binds to a polypeptide comprising the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:257 said method comprising contacting the polypeptide with an agent that binds to the polypeptide and assaying the complex formed with the agent bound to the polypeptide.

5. A method for modulating the proteolytic activity of an isolated polypeptide comprising the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:257 the method comprising contacting said polypeptide with an antibody under conditions that allow the antibody to modulate the proteolytic activity of the polypeptide.

6. An isolated nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:257, or a complement thereof.

7. A method for identifying a polynucleotide agent that modulates the expression of a nucleic acid molecule, wherein said nucleic acid molecule comprises the nucleotide sequence shown in SEQ ID NO:257, or the complement thereof, said method comprising contacting said nucleic acid molecule with the polynucleotide agent under conditions that allow the polynucleotide agent to modulate the expression or activity of said nucleic acid molecule.